56 results on '"Tatiana V. Lipina"'
Search Results
2. Uncoupling DISC1 × D2R Protein-Protein Interactions Facilitates Latent Inhibition in Disc1-L100P Animal Model of Schizophrenia and Enhances Synaptic Plasticity via D2 Receptors
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Tatiana V. Lipina, Nikolay A. Beregovoy, Alina A. Tkachenko, Ekaterina S. Petrova, Marina V. Starostina, Qiang Zhou, and Shupeng Li
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DISC1 ,D2R ,Disc1-L100P mouse model of schizophrenia ,latent inhibition ,synaptic plasticity ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Both Disrupted-In-Schizophrenia-1 (DISC1) and dopamine receptors D2R have significant contributions to the pathogenesis of schizophrenia. Our previous study demonstrated that DISC1 binds to D2R and such protein-protein interaction is enhanced in patients with schizophrenia and Disc1-L100P mouse model of schizophrenia (Su et al., 2014). By uncoupling DISC1 × D2R interaction (trans-activator of transcription (TAT)-D2pep), the synthesized TAT-peptide elicited antipsychotic-like effects in pharmacological and genetic animal models, without motor side effects as tardive dyskinesia commonly seen with typical antipsychotic drugs (APDs), indicating that the potential of TAT-D2pep of becoming a new APD. Therefore, in the current study, we further explored the APD-associated capacities of TAT-D2pep. We found that TAT-D2pep corrected the disrupted latent inhibition (LI), as a hallmark of schizophrenia associated endophenotype, in Disc1-L100P mutant mice—a genetic model of schizophrenia, supporting further APD’ capacity of TAT-D2pep. Moreover, we found that TAT-D2pep elicited nootropic effects in C57BL/6NCrl inbred mice, suggesting that TAT-D2pep acts as a cognitive enhancer, a desirable feature of APDs of the new generation. Namely, TAT-D2pep improved working memory in T-maze, and cognitive flexibility assessed by the LI paradigm, in C57BL/6N mice. Next, we assessed the impact of TAT-D2pep on hippocampal long-term plasticity (LTP) under basal conditions and upon stimulation of D2 receptors using quinpirole. We found comparable effects of TAT-D2pep and its control TAT-D2pep-scrambled peptide (TAT-D2pep-sc) under basal conditions. However, under stimulation of D2R by quinpirole, LTP was enhanced in hippocampal slices incubated with TAT-D2pep, supporting the notion that TAT-D2pep acts in a dopamine-dependent manner and acts as synaptic enhancer. Overall, our experiments demonstrated implication of DISC1 × D2R protein-protein interactions into mechanisms of cognitive and synaptic plasticity, which help to further understand molecular-cellular mechanisms of APD of the next generation.
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- 2018
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3. Ultrasonic Vocalizations in Mice During Exploratory Behavior are Context-Dependent.
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Ho-suk eMun, Tatiana V. Lipina, and John C. Roder
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Mouse ,exploration ,novelty ,Ultrasonic Vocalizations (USVs) ,Rearings ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
While rat ultrasonic vocalizations (USVs) are known to vary with anticipation of an aversive versus positive stimulus, little is known about USVs in adult mice in relation to behaviors. We recorded the calls of adult C57BL/6J male mice under different environmental conditions by exposing mice to both novel and familiar environments that varied in stress intensity through the addition of bright light or shallow water. In general, mouse USVs were significantly more frequent and of longer duration in novel environments. Particularly, mice in dimly-lit novel environments performed more USVs while exhibiting unsupported rearing and walking behavior, and these calls were mostly at high frequency. In contrast, mice exhibited more low frequency USVs when engaging in supported rearing behavior in novel environments. These findings are consistent with data from rats suggesting that low-frequency calls are made under aversive conditions and high-frequency calls occur in non-stressful conditions. Our finding increase understanding of acoustic signals associated with exploratory behaviors relevant to cognitive and motivational aspects of behavior.
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- 2015
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4. The habenular volume and PDE7A allelic polymorphism in major depressive disorder: preliminary findings
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Lyubomir I. Aftanas, Elena A. Filimonova, Maksim S. Anisimenko, Darya A. Berdyugina, Maria V. Rezakova, German G. Simutkin, Nikolay A. Bokhan, Svetlana A. Ivanova, Konstantin V. Danilenko, and Tatiana V. Lipina
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Psychiatry and Mental health ,Biological Psychiatry - Abstract
The habenula is a brain structure implicated in depression, yet with unknown molecular mechanisms. Several phosphodiesterases (PDEs) have been associated with a risk of depression. Although the role of PDE7A in the brain is unknown, it has enriched expression in the medial habenula, suggesting that it may play a role in depression. We analysed: (1) habenula volume assessed by 3-T magnetic resonance imaging (MRI) in 84 patients with major depressive disorder (MDD) and 41 healthy controls; (2) frequencies of 10 single nucleotide polymorphisms (SNPs) in PDE7A gene in 235 patients and 41 controls; and (3) both indices in 80 patients and 27 controls. The analyses considered gender, age, body mass index and season of the MRI examination. The analysis did not reveal habenula volumetric changes in MDD patients regardless of PDE7A SNPs. However, in the combined group, the carriers of one or more mutations among 10 SNPs in the PDE7A gene had a lower volume of the left habenula (driven mainly by rs972362 and rs138599850 mutations) and consequently had the reduced habenular laterality index in comparison with individuals without PDE7A mutations. Our findings suggest the implication of the PDE7A gene into mechanisms determining the habenula structure.
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- 2022
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5. Neuronal lack of PDE7a disrupted working memory, spatial learning, and memory but facilitated cued fear memory in mice
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Zizhen Liu, Axiang Li, Tahir Ali, Kaiwu He, Ruyan Gao, Liufang He, Hao Qiang, Tao Li, Ningning Li, Ana M. Garcia, Carmen Gil, Ana Martinez, Tatiana V. Lipina, Shupeng Li, Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Science and Technology Innovation Commission, Ali, Tahir [0000-0002-2138-1303], He, Kaiwu [0000-0002-8131-5850], Gil, Carmen [0000-0002-3882-6081], Martínez, Ana [0000-0002-2707-8110], Ali, Tahir, He, Kaiwu, Gil, Carmen, and Martínez, Ana
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Pharmacology ,Cyclic Nucleotide Phosphodiesterases, Type 7 ,Brain-Derived Neurotrophic Factor ,Spatial Learning ,Synaptophysin ,PDE7a ,Working memory ,Fear ,Contextual and cued fear memory ,AMP-Activated Protein Kinases ,Hippocampus ,Mice, Inbred C57BL ,Mice ,Memory, Short-Term ,Memory ,Animals ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Biological Psychiatry ,Spatial learning & memory - Abstract
12 p.-5 fig., Background: PDEs regulate cAMP levels which is critical for PKA activity-dependent activation of CREB-mediated transcription in learning and memory. Inhibitors of PDEs like PDE4 and Pde7 improve learning and memory in rodents. However, the role of PDE7 in cognition or learning and memory has not been reported yet., Methods:Therefore, we aimed to explore the cognitive effects of a PDE7 subtype, PDE7a, using combined pharmacological and genetic approaches., Results: PDE7a-nko mice showed deficient working memory, impaired novel object recognition, deficient spatial learning & memory, and contextual fear memory, contrary to enhanced cued fear memory, highlighting the potential opposite role of PDE7a in the hippocampal neurons. Further, pharmacological inhibition of PDE7 by AGF2.20 selectively strengthens cued fear memory in C57BL/6 J mice, decreasing its extinction but did not affect cognitive processes assessed in other behavioral tests. The further biochemical analysis detected deficient cAMP in neural cell culture with genetic excision of the PDE7a gene, as well as in the hippocampus of PDE7a-nko mice in vivo. Importantly, we found overexpression of PKA-R and the reduced level of pPKA-C in the hippocampus of PDE7a-nko mice, suggesting a novel mechanism of the cAMP regulation by PDE7a. Consequently, the decreased phosphorylation of CREB, CAMKII, eif2a, ERK, and AMPK, and reduced total level of NR2A have been found in the brain of PDE7a-nko animals. Notably, genetic excision of PDE7a in neurons was not able to change the expression of NR2B, BDNF, synapsin1, synaptophysin, or snap25., Conclusion: Altogether, our current findings demonstrated, for the first time, the role of PDE7a in cognitive processes. Future studies will untangle PDE7a-dependent neurobiological and molecular-cellular mechanisms related to cAMP-associated disorders., This work was supported by the Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions No: 2022SHIBS0004: Basic research and free exploration project of Shenzhen Science and technology innovation Commission (JCYJ20190808113007570).
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- 2022
6. Kainate receptor auxiliary subunit NETO2 is required for normal fear expression and extinction
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Juha Partanen, Iiris Hovatta, Ewa Sokolowska, Evgueni Ivakine, Natalia Kulesskaya, Emilie Rydgren, Vootele Voikar, Victoria B. Risbrough, Francesca Morello, Marie Mennesson, Tatiana V Lipina, Biosciences, Molecular and Integrative Biosciences Research Programme, Department of Psychology and Logopedics, Neuroscience Center, Developmental neurogenetics, University Management, Iiris Hovatta / Principal Investigator, Genetics, and Mind and Matter
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INVOLVEMENT ,DISORDER ,medicine.medical_specialty ,515 Psychology ,Hippocampus ,Kainate receptor ,Biology ,Amygdala ,03 medical and health sciences ,0302 clinical medicine ,GRIK2 ,Internal medicine ,medicine ,GRIK1 ,Fear conditioning ,Prefrontal cortex ,NEURONS ,RELEASE ,Pharmacology ,MEMORY ,3112 Neurosciences ,LOCALIZATION ,ASSOCIATION ,Extinction (psychology) ,030227 psychiatry ,AMYGDALA ,Psychiatry and Mental health ,Endocrinology ,medicine.anatomical_structure ,HIPPOCAMPUS ,biology.protein ,030217 neurology & neurosurgery - Abstract
NETO1 and NETO2 are auxiliary subunits of kainate receptors (KARs). They interact with native KAR subunits to modulate multiple aspects of receptor function. Variation in KAR genes has been associated with psychiatric disorders in humans, and in mice, knockouts of the Grik1 gene have increased, while Grik2 and Grik4 knockouts have reduced anxiety-like behavior. To determine whether the NETO proteins regulate anxiety and fear through modulation of KARs, we undertook a comprehensive behavioral analysis of adult Neto1(-/-) and Neto2(-/-) mice. We observed no differences in anxiety-like behavior. However, in cued fear conditioning, Neto2(-/-), but not Neto1(-/-) mice, showed higher fear expression and delayed extinction compared to wild type mice. We established, by in situ hybridization, that Neto2 was expressed in both excitatory and inhibitory neurons throughout the fear circuit including the medial prefrontal cortex, amygdala, and hippocampus. Finally, we demonstrated that the relative amount of synaptosomal KAR GLUK2/3 subunit was 20.8% lower in the ventral hippocampus and 36.5% lower in the medial prefrontal cortex in Neto2(-/-) compared to the Neto2(+/+) mice. The GLUK5 subunit abundance was reduced 23.8% in the ventral hippocampus and 16.9% in the amygdala. We conclude that Neto2 regulates fear expression and extinction in mice, and that its absence increases conditionability, a phenotype related to post-traumatic stress disorder and propose that this phenotype is mediated by reduced KAR subunit abundance at synapses of fear-associated brain regions.
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- 2019
7. Antipsychotics of New Generation: Where Are We Now?
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Shupeng Li, Tatiana V. Lipina, and Colm M. P. O’Tuathaigh
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medicine.medical_specialty ,neurodevelopment ,Schizophrenia (object-oriented programming) ,lcsh:RM1-950 ,hippocampal neural circuits ,animal models ,schizophrenia ,Editorial ,lcsh:Therapeutics. Pharmacology ,medicine ,Pharmacology (medical) ,genetics ,pharmacology ,Psychology ,Psychiatry - Published
- 2021
8. Effects of Specific Inhibitor of Phosphodiesterase 7 at the Late Stage of Long-Term Potentiation in Murine Hippocampal Slices
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N. A. Beregovoi, Tatiana V. Lipina, and M. V. Starostina
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Cyclic Nucleotide Phosphodiesterases, Type 7 ,Neuronal Plasticity ,Chemistry ,Long-Term Potentiation ,Excitatory Postsynaptic Potentials ,Phosphodiesterase ,Hippocampus ,Long-term potentiation ,General Medicine ,In Vitro Techniques ,Pharmacology ,Hippocampal formation ,General Biochemistry, Genetics and Molecular Biology ,Mice, Inbred C57BL ,Mice ,Synaptic plasticity ,Second messenger system ,Cyclic AMP ,Excitatory postsynaptic potential ,Animals ,Memory consolidation ,Enzyme Inhibitors ,Cyclic GMP - Abstract
Second messengers cAMP and cGMP play an important role in synaptic plasticity and memory consolidation. The inhibitors of phosphodiesterases, enzymes hydrolyzing these cyclic nucleotides, are actively studied as potential drugs for the treatment of various cognitive disorders and depression. We studied the effects of a new inhibitor of phosphodiesterase 7 AGF2.20 on the formation of long-term potentiation in hippocampal slices. Administration of AGF2.20 (10 nM) in 90 min after weak tetanization prevented a decrease in the amplitude of excitatory post-synaptic potentials and stabilized long-term potentiation. These data attest to the involvement of phosphodiesterase 7 in the development of synaptic plasticity in the hippocampus. The inhibitor AGF2.20 is considered for the further analysis as a promising substance for the treatment of cognitive impairments.
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- 2019
9. Proteomic and electron microscopy study of myogenic differentiation of alveolar mucosa multipotent mesenchymal stromal cells in three‐dimensional culture
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Arthur T. Kopylov, A.A. Gorkun, Andrey A. Pulin, Nastasia V. Kosheleva, Anna L. Kaysheva, Tatiana V. Lipina, I.M. Zurina, Svetlana S. Girina, Marina E. Krasina, Sergey G. Morozov, and Irina Saburina
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Proteomics ,education.field_of_study ,Mucous Membrane ,Chemistry ,Myogenesis ,Autophagy ,Population ,Spheroid ,Respiratory chain ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell morphology ,Biochemistry ,Cell biology ,Microscopy, Electron ,Spheroids, Cellular ,embryonic structures ,Myocyte ,Cytoskeleton ,education ,Molecular Biology ,Cells, Cultured - Abstract
Myocyte differentiation is featured by adaptation processes, including mitochondria repopulation and cytoskeleton re-organization. The difference between monolayer and spheroid cultured cells at the proteomic level is uncertain. We cultivated alveolar mucosa multipotent mesenchymal stromal cells in spheroids in a myogenic way for the proper conditioning of ECM architecture and cell morphology, which induced spontaneous myogenic differentiation of cells within spheroids. Electron microscopy analysis was used for the morphometry of mitochondria biogenesis, and proteomic was used complementary to unveil events underlying differences between two-dimensional/three-dimensional myoblasts differentiation. The prevalence of elongated mitochondria with an average area of 0.097 μm2 was attributed to monolayer cells 7 days after the passage. The population of small mitochondria with a round shape and area of 0.049 μm2 (p < 0.05) was observed in spheroid cells cultured under three-dimensional conditions. Cells in spheroids were quantitatively enriched in proteins of mitochondria biogenesis (DNM1L, IDH2, SSBP1), respiratory chain (ACO2, ATP5I, COX5A), extracellular proteins (COL12A1, COL6A1, COL6A2), and cytoskeleton (MYL6, MYL12B, MYH10). Most of the Rab-related transducers were inhibited in spheroid culture. The proteomic assay demonstrated delicate mechanisms of mitochondria autophagy and repopulation, cytoskeleton assembling, and biogenesis. Differences in the ultrastructure of mitochondria indicate active biogenesis under three-dimensional conditions.
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- 2021
10. Vocal and physical phenotypes of calsyntenin2 knockout mouse pups model early-life symptoms of the autism spectrum disorder
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Ilya A. Volodin, Anna V. Klenova, Tamara G. Amstislavskaya, Elena V. Volodina, Tatiana V. Lipina, and Svetlana V. Ranneva
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Male ,medicine.medical_specialty ,Autism Spectrum Disorder ,Period (gene) ,Biology ,Adhesion protein ,Mice ,03 medical and health sciences ,Behavioral Neuroscience ,Call rate ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Ultrasonics ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Calcium-Binding Proteins ,Membrane Proteins ,Acoustics ,medicine.disease ,Phenotype ,Early life ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,Autism spectrum disorder ,Knockout mouse ,Autism ,Female ,Vocalization, Animal ,030217 neurology & neurosurgery - Abstract
This study discovered a novel acoustic phenotype in Calsyntenin2 deficient knockout (Clstn2-KO) pups in the neurodevelopment period of 5-9 postnatal days (PND 5-9). The narrowband ultrasonic calls (nUSVs) were less complex (mostly one-note, shorter in duration and higher in peak frequency) in Clsnt2-KO than in wild-type (WT) C57BL/6 J pups. The wideband ultrasonic calls (wUSVs) were produced substantially more often by Clstn2-KO than WT pups. The clicks were longer in duration and higher in peak frequency and power quartiles in Clstn2-KO pups. The elevated discomfort due to additional two-minute maternal separation coupled with experimenter's touch, resulted in significantly higher call rates of both nUSVs and clicks in pups of both genotypes and sexes compared to the previous two-minute maternal separation, whereas the call rate of wUSVs was not affected. In Clstn2-KO pups, the prevalence of emission of wUSVs retained at both sex and both degrees of discomfort, thus providing a reliable quantitative acoustic indicator for this genetic line. Besides the acoustic differences, we also detected the increased head-to-body ratio in Clstn2-KO pups. Altogether, this study demonstrated that lack of such synaptic adhesion protein as calsyntenin2 affects neurodevelopment of vocalization in a mouse as a model organism.
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- 2021
11. Viral Load and Patterns of SARS-CoV-2 Dissemination to the Lungs, Mediastinal Lymph Nodes, and Spleen of Patients with COVID-19 Associated Lymphopenia
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T.V. Gasanova, Andrey Sudarikov, A. V. Volkov, A O Abdullaev, Yuri Lebedin, Akmaljon Odilov, Igor I. Babichenko, Tatiana V. Lipina, and Maxim Ershler
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Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Spleen ,Microbiology ,Article ,multiplex real-time polymerase chain reaction ,03 medical and health sciences ,COVID-19 Testing ,0302 clinical medicine ,hemic and lymphatic diseases ,Lymphopenia ,Virology ,medicine ,Humans ,Cytotoxic T cell ,skin and connective tissue diseases ,Lung ,Histiocyte ,Aged ,Aged, 80 and over ,SARS-CoV-2 ,business.industry ,Mediastinum ,COVID-19 ,Middle Aged ,Viral Load ,respiratory system ,Immunohistochemistry ,QR1-502 ,respiratory tract diseases ,body regions ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Spike Glycoprotein, Coronavirus ,Female ,Lymph Nodes ,Lymph ,business ,Multiplex Polymerase Chain Reaction ,Viral load - Abstract
Lymphopenia is a frequent hematological manifestation, associated with a severe course of COVID-19, with an insufficiently understood pathogenesis. We present molecular genetic immunohistochemical, and electron microscopic data on SARS-CoV-2 dissemination and viral load (VL) in lungs, mediastinum lymph nodes, and the spleen of 36 patients who died from COVID-19. Lymphopenia <, 1 × 109/L was observed in 23 of 36 (63.8%) patients. In 12 of 36 cases (33%) SARS-CoV-2 was found in lung tissues only with a median VL of 239 copies (range 18–1952) SARS-CoV-2 cDNA per 100 copies of ABL1. Histomorphological changes corresponding to bronchopneumonia and the proliferative phase of DAD were observed in these cases. SARS-CoV-2 dissemination into the lungs, lymph nodes, and spleen was detected in 23 of 36 patients (58.4%) and was associated with the exudative phase of DAD in most of these cases. The median VL in the lungs was 12,116 copies (range 810–250281), lymph nodes—832 copies (range 96–11586), and spleen—71.5 copies (range 0–2899). SARS-CoV-2 in all cases belonged to the 19A strain. A immunohistochemical study revealed SARS-CoV-2 proteins in pneumocytes, alveolar macrophages, and bronchiolar epithelial cells in lung tissue, sinus histiocytes of lymph nodes, as well as cells of the Billroth pulp cords and spleen capsule. SARS-CoV-2 particles were detected by transmission electron microscopy in the cytoplasm of the endothelial cell, macrophages, and lymphocytes. The infection of lymphocytes with SARS-CoV-2 that we discovered for the first time may indicate a possible link between lymphopenia and SARS-CoV-2-mediated cytotoxic effect.
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- 2021
12. Features of emotional and social behavioral phenotypes of calsyntenin2 knockout mice
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Tatiana V. Lipina, Tamara G. Amstislavskaya, Svetlana V. Ranneva, K.S. Pavlov, and A.V. Gromova
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Male ,0301 basic medicine ,Endophenotypes ,Emotions ,Motor Activity ,Affect (psychology) ,Open field ,Developmental psychology ,Marble burying ,Food Preferences ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Emotionality ,medicine ,Agonistic behaviour ,Animals ,Learning ,Autistic Disorder ,Social Behavior ,Mice, Knockout ,Sex Characteristics ,Calcium-Binding Proteins ,Membrane Proteins ,Recognition, Psychology ,medicine.disease ,Smell ,030104 developmental biology ,Knockout mouse ,Anxiety ,Autism ,Female ,medicine.symptom ,Psychology ,030217 neurology & neurosurgery - Abstract
Calsyntenin-2 (Clstn2) is the synaptic protein that belongs to the super family of cadherins, playing an important role in learning and memory. We recently reported that Clstn2 knockout mice (Clstn2-KO) have a deficit of GABAergic interneurons coupled with hyperactivity and deficient spatial memory. Given, that impaired functioning of GABA receptors is linked to several psychopathologies, including anxiety and autism, we sought to further characterize Clstn2-KO mice with respect to emotional and social behavior. Clstn2-KO males and females were tested in the elevated plus-maze (EPM), open field (OF), forced swim test, social affiliation and recognition test, social transmission of food preference (STFP), dyadic social interactions and marble burying test. Clstn2-KO mice demonstrated high exploration and hyperactivity in the dimly lit EPM that affect anxiety parameters. In contrast, in a more adverse situation in the OF have increased emotionality in Clstn2-KO males, not females. Assessment of hyperactivity for prolong period in the OF showed that Clstn2-KO animals were able to decline their hyperactivity, but their ambulation still remained higher than in WT littermates. Additionally, Clstn2-KO mice expressed stereotyped behavior. Strikingly, analysis of social behavior identified deficient social motivation and social recognition only in Clstn2-KO males, but not in females. Further analysis of social communication in the STFP and direct observation of agonistic interactions confirmed the reduced social behavior in Clstn2-KO males. Altogether, current results showed Clstn2 gene and sex interactions on socio-emotional performance in mice, suggesting a possible role of calsyntenin2 in psychopathological mechanisms of autism.
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- 2017
13. The role of the habenula in the transition from reward to misery in substance use and mood disorders
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Arnt F. A. Schellekens, Maartje Luijten, Guillaume Sescousse, Anton J. M. Loonen, Tatiana V. Lipina, Judith R. Homberg, Albert Batalla, and Svetlana A. Ivanova
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0301 basic medicine ,drug dependence ,fmri ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,resting state network ,GABAergic system ,Comorbidity ,Experimental Psychopathology and Treatment ,Behavioral Neuroscience ,0302 clinical medicine ,Basal ganglia ,Monoaminergic ,Epithalamus ,Prefrontal cortex ,prefrontal cortex ,Neuropsychology and Physiological Psychology ,Habenula ,priority journal ,brain nerve cell ,addiction ,Psychology ,Interpeduncular nucleus ,Substance-Related Disorders ,Cognitive Neuroscience ,brain region ,review ,mood disorder ,glutamatergic synapse ,cholinergic system ,brain function ,03 medical and health sciences ,Reward ,aversive behavior ,preclinical study ,Avoidance Learning ,medicine ,Animals ,Humans ,human ,Substance use disorders ,nonhuman ,Mood Disorders ,functional connectivity ,medicine.disease ,030104 developmental biology ,Rostromedial tegmental nucleus ,Mood disorders ,Neuroscience ,170 000 Motivational & Cognitive Control ,Developmental Psychopathology ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 173900.pdf (Publisher’s version ) (Closed access) The habenula (Hb) is an evolutionary well-conserved structure located in the epithalamus. The Hb receives inputs from the septum, basal ganglia, hypothalamus, anterior cingulate and medial prefrontal cortex, and projects to several midbrain centers, most importantly the inhibitory rostromedial tegmental nucleus (RMTg) and the excitatory interpeduncular nucleus (IPN), which regulate the activity of midbrain monoaminergic nuclei. The Hb is postulated to play a key role in reward and aversion processing across species, including humans, and to be implicated in the different stages of transition from recreational drug intake to addiction and co-morbid mood disorders. The Hb is divided into two anatomically and functionally distinct nuclei, the lateral (LHb) and the medial (MHb), which are primarily involved in reward-seeking (LHb) and misery-fleeing (MHb) behavior by controlling the RMTg and IPN, respectively. This review provides a neuroanatomical description of the Hb, discusses preclinical and human findings regarding its role in the development of addiction and co-morbid mood disorders, and addresses future directions in this area. 10 p.
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- 2017
14. Lack of synaptic protein, calsyntenin-2, impairs morphology of synaptic complexes in mice
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Irina M Korostyshevskaja, Tatiana V Lipina, Valeriy F Maksimov, and Svetlana V. Ranneva
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Cerebral Cortex ,0303 health sciences ,Chemistry ,Calcium-Binding Proteins ,Membrane Proteins ,Hippocampal formation ,Inhibitory postsynaptic potential ,Synaptic vesicle ,Hippocampus ,Synapse ,Mice, Inbred C57BL ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,Knockout mouse ,Synapses ,GABAergic ,Calsyntenin ,Animals ,Synaptic Vesicles ,Neuroscience ,Postsynaptic density ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Calsyntenin-2 (Clstn2) is the synaptic protein, which belongs to the superfamily of cadherins, playing an important role in learning and memory. We recently reported that Clstn2 knockout mice (Clstn2-KO) have a deficit of GABAergic interneurons, associated with hyperactivity, deficient spatial memory, and social behavior. Therefore, we sought to characterize morphometric features of the ultrastructure of synaptic complexes of hippocampal and cortical neurons in Clstn2-KO mice, using high magnification electron microscopy. Morphometric analysis revealed a reduction of symmetric (inhibitory) synaptic density, length of synaptic contacts, and postsynaptic density in neurons of Clstn2-KO mice. Moreover, cortical neurons of Clstn2-KO mice were characterized by the predominance of the simplified type of synapses with the emergence of negative curvature of the synaptic zone in Clstn2-KO mice. Notably, presynaptic zones of cortical neurons of Clstn2-KO mice were characterized by the increased number of synaptic vesicles in opposite to the decreased number of synaptic vesicles in the presynaptic zones of hippocampal neurons. Overall, we found that lack of calsyntenin-2 leads to the striking architectonic alterations of synaptic complexes in the mouse brain, disrupting synaptic density, shape, and connectivity.
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- 2019
15. Conditioned stimulus presentations alter anxiety level in fear-conditioned mice
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Tatiana V Lipina, Kunfu Ouyang, Yujie Zhang, Hong Wang, and Qiang Zhou
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Male ,0301 basic medicine ,medicine.medical_specialty ,Conditioning, Classical ,Heart rate ,Hypothalamus ,Calcium imaging ,Discriminative fear conditioning ,Cell-Penetrating Peptides ,Anxiety ,Hippocampal formation ,lcsh:RC346-429 ,Lipopeptides ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Basal (phylogenetics) ,Discrimination, Psychological ,0302 clinical medicine ,Internal medicine ,PKMzeta ,Animals ,Medicine ,Fear conditioning ,Freezing Reaction, Cataleptic ,Molecular Biology ,Protein Kinase C ,lcsh:Neurology. Diseases of the nervous system ,Neurons ,Diazepam ,business.industry ,Research ,Classical conditioning ,Fear ,Amygdala ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Calcium ,medicine.symptom ,business ,Ventral hippocampal CA1 ,030217 neurology & neurosurgery ,medicine.drug ,Basolateral amygdala - Abstract
It is generally believed that fear is rapidly triggered by a distinct cue while anxiety onset is less precise and not associated with a distinct cue. Although it has been claimed that both processes can be measured with certain independence of each other, it is unclear how exactly they differ. In this study, we measured anxiety in mice that received discriminative fear conditioning using behavioral, heart rate and calcium (Ca2+) responses in the ventral hippocampal CA1 (vCA1) neurons. We found that the occurrence of fear significantly interfered with anxiety measurements under various conditions. Diazepam reduced basal anxiety level but had no effect during the presentation of conditioned stimulus (CS). Injection of an inhibitory peptide of PKMzeta (ZIP) into the basolateral amygdala almost entirely abolished CS-triggered fear expression and reduced anxiety to basal level. Heart rate measures suggested a small reduction in anxiety during CS-. Calcium responses in the lateral hypothalamus-projecting vCA1 neurons showed a steady decay during CS suggesting a reduced anxiety. Thus, under our experimental conditions, CS presentations likely reduce anxiety level in the fear-conditioned mice. Electronic supplementary material The online version of this article (10.1186/s13041-019-0445-4) contains supplementary material, which is available to authorized users.
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- 2019
16. The increased density of the habenular neurons, high impulsivity, aggression and resistant fear memory in Disc1-Q31L genetic mouse model of depression
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Anastasia Serykh, M. V. Starostina, Tamara G. Amstislavskaya, Marina V. Khrapova, Ekaterina S. Petrova, Nina I Dubrovina, Tatiana V Lipina, and Nadezhda Mikhnevich
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Male ,Poison control ,Nerve Tissue Proteins ,Impulsivity ,Mice ,03 medical and health sciences ,Behavioral Neuroscience ,DISC1 ,0302 clinical medicine ,Memory ,medicine ,Animals ,Bipolar disorder ,030304 developmental biology ,Mice, Knockout ,Neurons ,Habenula ,0303 health sciences ,biology ,Fear ,medicine.disease ,Aggression ,Mice, Inbred C57BL ,Disease Models, Animal ,Mood ,Mood disorders ,Schizophrenia ,Impulsive Behavior ,biology.protein ,Female ,medicine.symptom ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Mood disorders affect nearly 300 million humans worldwide, and it is a leading cause of death from suicide. In the last decade, the habenula has gained increased attention due to its major role to modulate emotional behavior and related psychopathologies, including depression and bipolar disorder, through the modulation of monoamines' neurotransmission. However, it is still unclear which genetic factors may directly affect the function of the habenula and hence, could contribute to the psychopathological mechanisms of mood disorders. Disrupted-In-Schizophrenia-1 (DISC1) gene is among robust gene-candidates predisposing to major depression, bipolar disorder and schizophrenia in humans. DISC1-Q31L, a well-established genetic mouse model of depression, offers a unique opportunity for translational studies. The current study aimed to probe morphological features of the habenula in the DISC1-Q31L mouse line and detect novel behavioral endophenotypes, including the increased emotionality in mutant females, high aggression in mutant males and deficient extinction of fear memory in DISC1 mutant mice of both sexes. The histological analysis found the increased neural density in the lateral and medial habenula in DISC1-Q31L mice regardless of sex, hence, excluding direct association between the habenular neurons and emotionality in mutant females. Altogether, our findings demonstrated, for the first time, the direct impact of the DISC1 gene on the habenular neurons and affective behavior in the DISC1-Q31L genetic mouse line. These new findings suggest that the combination of the DISC1 genetic analysis together with habenular neuroimaging may improve diagnostics of mood disorder in clinical studies.
- Published
- 2020
17. A Dopamine D2 Receptor-DISC1 Protein Complex may Contribute to Antipsychotic-Like Effects
- Author
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Min Wang, Albert H.C. Wong, Stephen S. G. Ferguson, John C. Roder, Shupeng Li, Ping Su, Tatiana V. Lipina, Paul J. Fletcher, Hailong Zhang, Sheng Chen, Terence K. Y. Lai, José N. Nobrega, Dongxu Zhai, Fang Liu, and Frankie H. F. Lee
- Subjects
Male ,medicine.medical_specialty ,Arrestins ,medicine.medical_treatment ,Neuroscience(all) ,Nerve Tissue Proteins ,Pharmacology ,Motor Activity ,DISC1 ,Glycogen Synthase Kinase 3 ,Mice ,Extrapyramidal symptoms ,GSK-3 ,Internal medicine ,Dopamine receptor D2 ,medicine ,Animals ,Humans ,Phosphorylation ,Antipsychotic ,Receptor ,beta-Arrestins ,Catalepsy ,biology ,Prepulse Inhibition ,Receptors, Dopamine D2 ,General Neuroscience ,Brain ,medicine.disease ,Clathrin ,3. Good health ,Rats ,Amphetamine ,Endocrinology ,Schizophrenia ,Mutation ,biology.protein ,medicine.symptom ,Signal transduction ,Psychology ,Peptides ,Antipsychotic Agents ,Protein Binding - Abstract
Summary Current antipsychotic drugs primarily target dopamine D2 receptors (D2Rs), in conjunction with other receptors such as those for serotonin. However, these drugs have serious side effects such as extrapyramidal symptoms (EPS) and diabetes. Identifying a specific D2R signaling pathway that could be targeted for antipsychotic effects, without inducing EPS, would be a significant improvement in the treatment of schizophrenia. We report here that the D2R forms a protein complex with Disrupted in Schizophrenia 1 (DISC1) that facilitates D2R-mediated glycogen synthase kinase (GSK)-3 signaling and inhibits agonist-induced D2R internalization. D2R-DISC1 complex levels are increased in conjunction with decreased GSK-3α/β (Ser21/9) phosphorylation in both postmortem brain tissue from schizophrenia patients and in Disc1 -L100P mutant mice, an animal model with behavioral abnormalities related to schizophrenia. Administration of an interfering peptide that disrupts the D2R-DISC1 complex successfully reverses behaviors relevant to schizophrenia but does not induce catalepsy, a strong predictor of EPS in humans. Video Abstract
- Published
- 2014
- Full Text
- View/download PDF
18. Disrupted-In-Schizophrenia-1 (DISC1) interactome and mental disorders: Impact of mouse models
- Author
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John C. Roder and Tatiana V. Lipina
- Subjects
Disease gene ,Network medicine ,biology ,Mental Disorders ,Cognitive Neuroscience ,Nerve Tissue Proteins ,Bioinformatics ,Interactome ,Disease Models, Animal ,Mice ,Behavioral Neuroscience ,DISC1 ,Neuropsychology and Physiological Psychology ,Behavioural phenotype ,biology.protein ,Animals ,Humans ,Neuroscience - Abstract
Disrupted-In-Schizophrenia-1 (DISC1) has captured much attention because it predisposes individuals to a wide range of mental illnesses. Notably, a number of genes encoding proteins interacting with DISC1 are also considered to be relevant risk factors of mental disorders. We reasoned that the understanding of DISC1-associated mental disorders in the context of network principles will help to address fundamental properties of DISC1 as a disease gene. Systematic integration of behavioural phenotypes of genetic mouse lines carrying perturbation in DISC1 interacting proteins would contribute to a better resolution of neurobiological mechanisms of mental disorders associated with the impaired DISC1 interactome and lead to a development of network medicine. This review also makes specific recommendations of how to assess DISC1 associated mental disorders in mouse models and discuss future directions.
- Published
- 2014
19. Maternal Immune Activation during Gestation Interacts withDisc1Point Mutation to Exacerbate Schizophrenia-Related Behaviors in Mice
- Author
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Daniela Hlousek, John C. Roder, Albert H.C. Wong, Clement C. Zai, and Tatiana V. Lipina
- Subjects
Reflex, Startle ,Offspring ,medicine.medical_treatment ,Transgene ,Mice, Transgenic ,Nerve Tissue Proteins ,Biology ,Mice ,DISC1 ,Pregnancy ,medicine ,Animals ,Point Mutation ,Maze Learning ,Social Behavior ,Prepulse inhibition ,Analysis of Variance ,General Neuroscience ,Point mutation ,Recognition, Psychology ,Articles ,Mice, Inbred C57BL ,Disease Models, Animal ,Poly I-C ,Cytokine ,Acoustic Stimulation ,Prenatal Exposure Delayed Effects ,Immunology ,Schizophrenia ,biology.protein ,Cytokines ,Female ,Animal studies ,Antibody - Abstract
Schizophrenia is thought to result from interactions between susceptible genotypes and environmental risk factors.DISC1is an important gene for schizophrenia and mood disorders based on both human and animal studies. In the present study we sought to investigate interactions between two distinct point mutations in the mouseDisc1gene (L100P and Q31L) and maternal immune activation (MIA) during pregnancy with polyinosinic:polycytidylic acid (polyI:C). PolyI:C given at 5 mg/kg impaired cognitive and social behavior in both wild-type (WT) andDisc1-Q31L+/−offspring, and reduced prepulse inhibition at 16 but not 8 weeks of age.Disc1-L100P+/−mutants were more sensitive to MIA than WT or Disc1-Q31L+/−mice. Interleukin-6 (IL-6) is a critical cytokine for mediating the behavioral and transcriptional effects of polyI:C. We found a more pronounced increase of IL-6 in response to polyI:C in fetal brain inDisc1-L100P+/−mice compared with WT orDisc1-Q31L+/−mice. Coadministration of an anti-IL-6 antibody with polyI:C reversed schizophrenia-related behavioral phenotypes inDisc1-L100P+/−mice. In summary, we found specific interactions between discrete genetic (Disc1-L100P+/−) and environmental factors (MIA) that exacerbate schizophrenia-related phenotypes. IL-6 may be important in the pathophysiology of this interaction.
- Published
- 2013
20. Co-learning facilitates memory in mice: A new avenue in social neuroscience
- Author
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Tatiana V. Lipina and John C. Roder
- Subjects
Male ,Mice, Inbred Strains ,Mice ,Cellular and Molecular Neuroscience ,Cognition ,Social neuroscience ,Memory ,Conditioning, Psychological ,medicine ,Animals ,Learning ,Fear conditioning ,Autistic Disorder ,Habituation ,Habituation, Psychophysiologic ,Social Behavior ,Episodic memory ,Pharmacology ,Cued speech ,Memory Disorders ,Behavior, Animal ,Social Behavior Disorders ,Recognition, Psychology ,medicine.disease ,Social learning ,Mice, Inbred C57BL ,Disease Models, Animal ,Exploratory Behavior ,Autism ,Vocalization, Animal ,Cognition Disorders ,Psychology ,Cognitive psychology - Abstract
Social context affects brain function but our understanding of its neurobiology is at an early stage. The mere presence of one individual can alter the cognitive capacities of another and social learning has been demonstrated in many species, including the mouse. We asked several questions: 1. How can active engagement of two familiar mice in the same learning activity (co-learning) alter their memory? 2. Under which environmental conditions (aversive vs non-aversive) can we expect the memory to be enhanced, impaired, or not affected? 3. Can a genetic factor modify the co-learning effect on memory? More specifically, can co-learning correct memory deficits in autistic-like BTBR inbred mice with deficient sociability? We demonstrated that pairs of familiar inbred mice of the same or different genotypes (C57BL/6J and BTBR) that were habituated to new objects and their spatial location, had enhanced episodic memory in the spatial object recognition test, whereas individually-trained animals failed to solve this task. Notably, the co-learning effect was genotype-dependent. BTBR mice paired with BTBR cage-mates in the habituation session modestly ameliorated their performance in the object recognition test but co-learning with a familiar C57BL/6J mouse completely normalized episodic memory deficit. Next, we explored the co-learning effect on fear memory in these inbred strains. Interestingly, mice of both genotypes displayed significantly enhanced contextual fear memory once they had been conditioned together with BTBR animals. The same influence of BTBR presence was observed on cued fear memory in C57BL/6J mice, whereas a modest co-learning effect was found on cued fear conditioning in the BTBR strain. Taken together, we demonstrated for the first time the co-learning effect on cognitive capacities in mice, which can be modified by genetic background and environmental conditions. The possible implications of this methodological approach in social neuroscience are discussed. This article is part of a Special Issue entitled ‘Cognitive Enhancers’.
- Published
- 2013
21. Drug Discovery for Schizophrenia
- Author
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Tatiana V Lipina, John C Roder, Tatiana V Lipina, and John C Roder
- Subjects
- Schizophrenia--Chemotherapy, Drugs--Design, Schizophrenia--drug therapy, Drug Discovery, Antipsychotic Agents
- Abstract
Since the pioneering pharmacotherapy for treatment of schizophrenia in the 1950s by antipsychotics, only a few major innovations have been made, pointing to a general stagnation in the field of pharmacology of schizophrenia. Drug Discovery for Schizophrenia covers new insights in the field of schizophrenia with an aim to advance the understanding of scientists and clinicians in this area and to fuel drug discovery. The book outlines a change in the way schizophrenia is treated by moving away from focusing only on treating symptoms in patients. Innovative drugs emerge from deeper comprehension of the pathological processes that emerge earlier in life, hence, providing strategies for preventative therapy to alter the course of this mental disorder. Amongst other current topics, the book covers new findings in genetics and epigenetics, progress in animal models for schizophrenia and the usage of induced pluripotent stem cells. The combination of these important areas benefit psychiatric neuroscience, filling the gaps in the knowledge of neurobiology of schizophrenia and providing novel perspectives for future drug development.
- Published
- 2015
22. Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition
- Author
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Fang Liu, Tatiana V. Lipina, John Georgiou, Dongxu Zhai, Steven J. Clapcote, Enoch Ng, John C. Roder, Christina Elliott, Ryan T. Cameron, Jonathan G. L. Mullins, George S. Baillie, Ahmed H Al-Amri, Ho Suk Mun, and Alexander McGirr
- Subjects
Male ,0301 basic medicine ,Arrestins ,Dendritic Spines ,Neurogenesis ,Conditioning, Classical ,Hippocampus ,Mice, Transgenic ,Nerve Tissue Proteins ,Anxiety ,Amygdala ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Memory ,Neuroplasticity ,Cyclic AMP ,medicine ,Animals ,Phosphorylation ,Cyclic AMP Response Element-Binding Protein ,beta-Arrestins ,Neurons ,Pharmacology ,Mice, Inbred BALB C ,Neuronal Plasticity ,Beta-Arrestins ,Phosphodiesterase ,Fear ,Cyclic nucleotide phosphodiesterases ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Mice, Inbred C57BL ,Psychiatry and Mental health ,030104 developmental biology ,medicine.anatomical_structure ,Exploratory Behavior ,Original Article ,Female ,Memory acquisition ,Erratum ,Psychology ,Cyclic AMP metabolism ,Neuroscience ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modeling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioral assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 h, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signaling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the prepulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory.
- Published
- 2016
23. Inhibition of glycogen synthase kinase 3 prevents synaptic long-term depression and facilitates cognition in C57BL/6J mice
- Author
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TATIANA V. LIPINA, MARIA JEKIELEK, NIKOLAY A. BEREGOVOY, MARINA V. STAROSTINA, VALLE PALOMO, DANIEL I PEREZ, ANA MARTINEZ, and JOHN C RODER
- Subjects
GSK-3 INHIBITOR,WORKING MEMORY,SPATIAL LEARNING & MEMORY,EXECUTIVE FUNCTION,SPATIAL OBJECT RECOGNITION,SYNAPTIC LONG-TERM DEPRESSION,MICE - Abstract
Glycogen synthase kinase 3 (GSK-3) is an important molecular player involved into diverse cellular functions including metabolism, transcription, cell survival and synaptic plasticity. Here, we focused on characterization of the cognitive effects of GSK-3 inhibitor, a newly developed compound VP3.36. In particular, we assessed VP3.36 effects on working memory, episodic memory, executive functioning, spatial learning & memory and fear memory. VP3.36 (3 mg/ kg) significantly enhanced working memory and spatial object recognition in C57BL/6J mice. The GSK-3 inhibitor was able to speed up solving obstacles given to experimental animals in the Puzzle test, thereby improving their executive functions. Lastly, VP3.36-treated mice learnt faster to find the escape platform in the Morris' water maze and exhibited better spatial long-term memory than vehicle-treated animals. At the same time, GSK-3 inhibition did not affect fear memories, sensorimotor gating, emotional behavior or ambulation, suggesting that GSK-3 inhibition underlies specific cognitive processes, which are likely coupled with certain mechanisms of synaptic plasticity. Given that GSK-3 inhibition has clear effect on long-term depression (LTD), and the functional role of LTD in brain is still far from complete understanding, next, we probed effects of VP3.36 on synaptic LTD in the hippocampal CA1 subregion. We found that incubation of hippocampal slices with VP3.36 sufficiently prevented synaptic LTD, further supporting implication of GSK-3 into mechanisms of synaptic plasticity. Taken together, VP3.36 facilitated working memory, spatial episodic and long-term memory, enhanced executive functions in parallel with its ability to prevent synaptic LTD. Overall, our experiments showed implication of GSK-3 into mechanisms of synaptic plasticity and certain cognitive functions which help to deeper understand fundamental molecular-cellular mechanisms of cognitive enhancement's processes.
- Published
- 2016
24. Social defeat interacts with Disc1 mutations in the mouse to affect behavior
- Author
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John C. Roder, Albert H.C. Wong, F. Nipa Haque, and Tatiana V. Lipina
- Subjects
Male ,Sucrose ,Elevated plus maze ,Startle response ,Time Factors ,Conditioning, Classical ,Mice, Transgenic ,Nerve Tissue Proteins ,Motor Activity ,Developmental psychology ,Social defeat ,Eating ,Mice ,Behavioral Neuroscience ,DISC1 ,Latent inhibition ,medicine ,Animals ,Interpersonal Relations ,Amino Acids ,Maze Learning ,Genetics ,Analysis of Variance ,Behavior, Animal ,medicine.diagnostic_test ,biology ,Environmental stressor ,Acoustics ,Fear ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Acoustic Stimulation ,Schizophrenia ,Mutation ,biology.protein ,Major depressive disorder ,Gene-Environment Interaction ,Psychology ,Stress, Psychological - Abstract
DISC1 (Disrupted-in-schizophrenia 1) is a strong candidate susceptibility gene for psychiatric disease that was originally discovered in a family with a chromosomal translocation severing this gene. Although the family members with the translocation had an identical genetic mutation, their clinical diagnosis and presentation varied significantly. Gene–environment interactions have been proposed as a mechanism underlying the complex heritability and variable phenotype of psychiatric disorders such as major depressive disorder and schizophrenia. We hypothesized that gene–environment interactions would affect behavior in a mutant Disc1 mouse model. We examined the effect of chronic social defeat (CSD) as an environmental stressor in two lines of mice carrying different Disc1 point mutations, on behaviors relevant to psychiatric illness: locomotion in a novel open field (OF), pre-pulse inhibition (PPI) of the acoustic startle response, latent inhibition (LI), elevated plus maze (EPM), forced swim test (FST), sucrose consumption (SC), and the social interaction task for sociability and social novelty (SSN). We found that Disc1-L100P +/− and wild-type mice have similar anxiety responses to CSD, while Q31L +/− mice had a very different response. We also found evidence of significant gene–environment interactions in the OF, EPM and SSN.
- Published
- 2012
25. Synergistic interactions between PDE4B and GSK-3: DISC1 mutant mice
- Author
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John C. Roder, Tatiana V. Lipina, Fang Liu, and Min Wang
- Subjects
Male ,medicine.medical_specialty ,Mutant ,Nerve Tissue Proteins ,Motor Activity ,Pharmacology ,Glycogen Synthase Kinase 3 ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,DISC1 ,0302 clinical medicine ,PDE4B ,GSK-3 ,Internal medicine ,Thiadiazoles ,Genetic model ,medicine ,Animals ,Glycogen synthase ,Rolipram ,030304 developmental biology ,0303 health sciences ,biology ,Genetic Variation ,Mice, Mutant Strains ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,3. Good health ,Mice, Inbred C57BL ,Endocrinology ,biology.protein ,Phosphodiesterase 4 Inhibitors ,Psychology ,030217 neurology & neurosurgery ,Protein Binding ,medicine.drug ,Behavioural despair test - Abstract
Disrupted-In-Schizophrenia-1 (DISC1) is a strong genetic risk factor associated with psychiatric disorders. Two distinct mutations in the second exon of the DISC1 gene (Q31L and L100P) lead to either depression- or schizophrenia-like behavior in mice. Both phosphodiesterase-4B (PDE4B) and glycogen synthase kinase-3 (GSK-3) have common binding sites on N-terminal region of DISC1 and are implicated into etiology of schizophrenia and depression. It is not known if PDE4B and GSK-3 could converge signals in the cell via DISC1 at the same time. The purpose of the present study was to assess whether rolipram (PDE4 inhibitor) might synergize with TDZD-8 (GSK-3 blocker) to produce antipsychotic effects at low doses on the DISC1-L100P genetic model. Indeed, combined treatment of DISC1-L100P mice with rolipram (0.1 mg/kg) and TDZD-8 (2.5 mg/kg) in sub-threshold doses corrected their Pre-Pulse Inhibition (PPI) deficit and hyperactivity, without any side effects at these doses. We have suggested that rolipram-induced increase of cAMP level might influence GSK-3 function and, hence the efficacy of TDZD-8. Our second goal was to estimate how DISC1-Q31L with reduced PDE4B activity, and therefore mimicking rolipram-induced conditions, could alter pharmacological response to TDZD-8, GSK-3 activity and its interaction with DISC1. DISC1-Q31L mutants showed increased sensitivity to GSK-3 inhibitor compare to DISC1-L100P mice. TDZD-8 (2.5 mg/kg) was able to correct PPI deficit, reduce immobility in the forced swim test (FST) and increased social motivation/novelty. In parallel, biochemical analysis revealed significantly reduced binding of GSK-3 to the mutated DISC1-Q31L and increased enzymatic activity of GSK-3. Taken together, genetic variations in DISC1 influence formation of biochemical complex with PDE4 and GSK-3 and strength the possibility of synergistic interactions between these proteins. This article is part of a Special Issue entitled ‘Schizophrenia’.
- Published
- 2012
26. Parametric and pharmacological modulations of latent inhibition in mouse inbred strains
- Author
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Tatiana V. Lipina, Russell Rasquinha, and John C. Roder
- Subjects
Male ,medicine.medical_treatment ,Clinical Biochemistry ,Mice, Inbred Strains ,Pharmacology ,Toxicology ,Biochemistry ,Mice ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Latent inhibition ,Inbred strain ,Desipramine ,medicine ,Haloperidol ,Animals ,Attention ,Antipsychotic ,Amphetamine ,Biological Psychiatry ,Clozapine ,Dose-Response Relationship, Drug ,Chemistry ,Amphetamines ,030227 psychiatry ,NMDA receptor ,Neuroscience ,030217 neurology & neurosurgery ,Antipsychotic Agents ,medicine.drug - Abstract
Latent inhibition (LI) is a cross species selective attention phenomenon, which is disrupted by amphetamine and enhanced by antipsychotic drugs (APDs). Accumulating data of LI in gene-modified mice as well as in mouse inbred strains suggest genetic component of LI. Here we study modulation of LI in mouse inbred strains with spontaneously disrupted LI by parametric manipulations (number of pre-exposures and conditioning trials) and pharmacological treatments with antipsychotics and NMDA modulator, D-serine. C3H/He and CBA/J inbred mice showed disrupted LI under conditions with 40 pre-exposures (PE) and 2 trials of the conditioned stimulus–unconditioned stimulus (CS–US) due to either loss of the pre-exposure effect or a ceiling effect of poor learning, respectively. The increased number of pre-exposures and/or number of conditioning trials corrected expression of LI in these inbred mice. The disrupted LI was also reversed by haloperidol in both inbred strains at 1.2 mg/kg but not at 0.4 mg/kg, as well as by clozapine (at 3 mg/kg in C3H/He and at 9 mg/kg in CBA/J mice). D-serine potentiated LI in C3H/He mice at 600 mg/kg, but not in the CBA/J at both studied doses (600 and 1800 mg/kg). Desipramine (10 mg/kg) had no effect on LI in both inbred mouse strains. Our findings demonstrated some resemblance between the effects of parametric and pharmacological manipulations on LI, suggesting that APDs may affect the capacity of the brain processes environmental stimuli in LI. Taken together, LI may offer a translational strategy that allows prediction of drug efficacy for cognitive impairments in schizophrenia.
- Published
- 2011
27. Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia
- Author
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Viviane Labrie, Tatiana V. Lipina, and John C. Roder
- Subjects
Male ,medicine.medical_specialty ,Psychosis ,medicine.drug_class ,Glycine ,Atypical antipsychotic ,Nerve Tissue Proteins ,Quinolones ,Receptors, N-Methyl-D-Aspartate ,Mice ,Glycine binding ,Internal medicine ,Serine ,medicine ,Animals ,Social Behavior ,Clozapine ,Glycine receptor ,Pharmacology ,Behavior, Animal ,business.industry ,Recognition, Psychology ,Sarcosine ,medicine.disease ,Mice, Mutant Strains ,Mice, Inbred C57BL ,Disease Models, Animal ,Phenotype ,Endocrinology ,Schizophrenia ,Space Perception ,NMDA receptor ,Schizophrenic Psychology ,Carrier Proteins ,business ,medicine.drug - Abstract
Schizophrenic patients demonstrate prominent negative and cognitive symptoms that are poorly responsive to antipsychotic treatment. Abnormal glutamatergic neurotransmission may contribute to these pathophysiological dimensions of schizophrenia.We examined the involvement of the glycine coagonist site on the N-methyl-D: -aspartate receptor (NMDAR) glycine coagonist site in the modulation of negative and cognitive endophenotypes in mice.Behavioral phenotypes relevant to schizophrenia were assessed in Grin1(D481N) mice that have reduced NMDAR glycine affinity.Grin1(D481N) mutant mice showed abnormally persistent latent inhibition (LI) that was reversed by two agents that enhance NMDAR glycine site function, D: -serine (600 mg/kg) and ALX-5407 (1 mg/kg), and by the classical atypical antipsychotic clozapine (3 mg/kg). Similarly, blockade of the NMDAR glycine site with the antagonist L-701,324 (5 mg/kg) induced persistent LI in C57BL6/J mice. In a social affiliations task, Grin1(D481N) mutant animals showed reduced social approach behaviors that were normalized by D: -serine (600 mg/kg). During a nonassociative spatial object recognition task, mutant mice demonstrated impaired reactivity to a spatial change that was reversible by D: -serine (300 and 600 mg/kg) and clozapine (0.75 mg/kg). In contrast, responses to social novelty and nonspatial change remained unaffected, indicating that the Grin1(D481N) mutation induces selective deficits in sociability and spatial discrimination, while leaving intact the ability to react to novelty.Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia. Antipsychotics that target the NMDAR glycine site may be beneficial in treating such psychiatric symptoms.
- Published
- 2008
28. Absence of the proapoptotic Bax protein extends fertility and alleviates age-related health complications in female mice
- Author
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Tatiana V. Lipina, Marc D. Grynpas, Gloria I. Perez, Andrea Jurisicova, Allison R. Bechard, Jonathan L. Tilly, Marijana Kanisek, John C. Roder, Patricia A. Hunt, Lisa Wise, and Yasushi Takai
- Subjects
Aging ,medicine.medical_specialty ,Ovariectomy ,media_common.quotation_subject ,Ovary ,Fertility ,Bone and Bones ,Mice ,Cognition ,Bcl-2-associated X protein ,Cataracts ,Quality of life ,Internal medicine ,medicine ,Animals ,bcl-2-Associated X Protein ,media_common ,Mice, Knockout ,Multidisciplinary ,Behavior, Animal ,biology ,Biological Sciences ,medicine.disease ,Menopause ,medicine.anatomical_structure ,Endocrinology ,Body Composition ,biology.protein ,Anxiety ,Female ,Perception ,medicine.symptom ,Human Females - Abstract
The menopausal transition in human females, which is driven by a loss of cyclic ovarian function, occurs around age 50 and is thought to underlie the emergence of an array of health problems in aging women. Although mice do not undergo a true menopause, female mice exhibit ovarian failure long before death because of chronological age and subsequently develop many of the same age-associated health complications observed in postmenopausal women. Here we show in mice that inactivation of the proapoptotic Bax gene, which sustains ovarian lifespan into advanced age, extends fertile potential and minimizes many age-related health problems, including bone and muscle loss, excess fat deposition, alopecia, cataracts, deafness, increased anxiety, and selective attention deficit. Further, ovariectomy studies show that the health benefits gained by aged females from Bax deficiency reflect a complex interplay between ovary-dependent and -independent pathways. Importantly, and contrary to popular belief, prolongation of ovarian function into advanced age by Bax deficiency did not lead to an increase in tumor incidence. Thus, the development of methods for postponing ovarian failure at menopause may represent an attractive option for improving the quality of life in aging females.
- Published
- 2007
29. Disrupted-in-Schizophrenia-1 (DISC1) Interactome and Schizophrenia
- Author
-
Tatiana V. Lipina and John C. Roder
- Subjects
DISC1 ,Preventive therapy ,biology ,Schizophrenia (object-oriented programming) ,Endophenotype ,mental disorders ,biology.protein ,Epigenetics of schizophrenia ,Context (language use) ,Mechanisms of schizophrenia ,behavioral disciplines and activities ,Neuroscience ,Interactome - Abstract
Disrupted-in-schizophrenia-1 (DISC1) has captured much attention, because it predisposes individuals to such a psychiatric disorder as schizophrenia. Notably, a number of genes encoding proteins that interact with DISC1 are also considered to be relevant risk factors for this mental disorder. Accumulating studies reveal a role of DISC1 and its interacting proteins in early neurodevelopment and the regulation of synaptic functioning. We reason that the understanding of schizophrenia in the context of the DISC1 interactome will help to understand the neurobiological mechanisms of schizophrenia. Given that DISC1 is associated with a wide range of endophenotypes, systematic integration of the functional roles of each of the DISC1 interacting proteins would contribute to a better resolution of the neurobiological mechanisms of schizophrenia and ultimately lead to the development of preventive therapy.
- Published
- 2015
30. Drug Discovery for Schizophrenia
- Author
-
Tatiana V. Lipina and John C. Roder
- Subjects
medicine.medical_specialty ,Chemistry ,Drug discovery ,Schizophrenia (object-oriented programming) ,medicine ,Psychiatry - Abstract
Since the pioneering pharmacotherapy for treatment of schizophrenia in the 1950s by antipsychotics, only a few major innovations have been made, pointing to a general stagnation in the field of pharmacology of schizophrenia. Drug Discovery for Schizophrenia covers new insights in the field of schizophrenia with an aim to advance the understanding of scientists and clinicians in this area and to fuel drug discovery. The book outlines a change in the way schizophrenia is treated by moving away from focusing only on treating symptoms in patients. Innovative drugs emerge from deeper comprehension of the pathological processes that emerge earlier in life, hence, providing strategies for preventative therapy to alter the course of this mental disorder. Amongst other current topics, the book covers new findings in genetics and epigenetics, progress in animal models for schizophrenia and the usage of induced pluripotent stem cells. The combination of these important areas benefit psychiatric neuroscience, filling the gaps in the knowledge of neurobiology of schizophrenia and providing novel perspectives for future drug development.
- Published
- 2015
31. The Ampakine CX546 Restores the Prepulse Inhibition and Latent Inhibition Deficits in mGluR5-Deficient Mice
- Author
-
Karin Weiss, John C. Roder, and Tatiana V. Lipina
- Subjects
Ampakine ,Reflex, Startle ,medicine.drug_class ,Receptor, Metabotropic Glutamate 5 ,animal diseases ,Conditioning, Classical ,Dioxoles ,Pharmacology ,Receptors, Metabotropic Glutamate ,Mice ,Latent inhibition ,Piperidines ,mental disorders ,medicine ,Animals ,Drug Interactions ,Prepulse inhibition ,Mice, Knockout ,Analysis of Variance ,Electroshock ,Behavior, Animal ,Dose-Response Relationship, Drug ,Metabotropic glutamate receptor 5 ,Chemistry ,Dose-Response Relationship, Radiation ,Neural Inhibition ,Antidepressive Agents ,Pyrrolidinones ,Aniracetam ,Mice, Inbred C57BL ,Dizocilpine ,Psychiatry and Mental health ,Acoustic Stimulation ,nervous system ,Knockout mouse ,NMDA receptor ,Dizocilpine Maleate ,Excitatory Amino Acid Antagonists ,medicine.drug - Abstract
In order to test the possible role of mGluR5 signaling in the behavioral endophenotypes of schizophrenia and other psychiatric disorders, we used genetic engineering to create mice carrying null mutations in this gene. Compared to their mGluR5(+/+) littermates, mGluR5(-/-) mice have disrupted latent inhibition (LI) as measured in a thirst-motivated conditioned emotional response procedure. Administration of the positive modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPAR), CX546, during the conditioning phase only, improved the disrupted LI in mGluR5 knockout mice and facilitated LI in control C57BL/6J mice, given extended number of conditioning trails (four conditioning stimulus-unconditioned stimulus). Prepulse inhibition (PPI) was impaired in mGluR5(-/-) mice to a level that could not be disrupted further by the antagonist of N-methyl-D-aspartate receptors - MK-801. PPI deficit of mGluR5(-/-) mice was effectively reversed by CX546, whereas aniracetam had a less pronounced effect. These data provide evidence that a potent positive AMPAR modulator can elicit antipsychotic action and represents a new approach for treatment of schizophrenia.
- Published
- 2006
32. In VivoMagnetic Resonance Imaging and Semiautomated Image Analysis Extend the Brain Phenotype forcdf/cdfMice
- Author
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Tatiana V. Lipina, John C. Roder, Susan L. Ackerman, R. Mark Henkelman, Natasa Kovacevic, and Nicholas A. Bock
- Subjects
Male ,Inferior colliculus ,Cerebellum ,Pathology ,medicine.medical_specialty ,Mutant ,Contrast Media ,Mice, Transgenic ,Biology ,Mice ,Mice, Neurologic Mutants ,Imaging, Three-Dimensional ,Chlorides ,In vivo ,Image Interpretation, Computer-Assisted ,medicine ,Animals ,medicine.diagnostic_test ,General Neuroscience ,Brain ,Magnetic resonance imaging ,Articles ,Magnetic Resonance Imaging ,Phenotype ,medicine.anatomical_structure ,Manganese Compounds ,Cytoarchitecture ,Female ,Neuroscience ,Neuroanatomy - Abstract
Magnetic resonance imaging and computer image analysis in human clinical studies effectively identify abnormal neuroanatomy in disease populations. As more mouse models of neurological disorders are discovered, such an approach may prove useful for translational studies. Here, we demonstrate the effectiveness of a similar strategy for mouse neuroscience studies by phenotyping mice with the cerebellar deficient folia (cdf) mutation. Usingin vivomultiple-mouse magnetic resonance imaging for increased throughput, we imaged groups ofcdfmutant, heterozygous, and wild-type mice and made an atlas-based segmentation of the structures in 15 individual brains. We then performed computer automated volume measurements on the structures. We found a reduced cerebellar volume in thecdfmutants, which was expected, but we also found a new phenotype in the inferior colliculus and the olfactory bulbs. Subsequent local histology revealed additional cytoarchitectural abnormalities in the olfactory bulbs. This demonstrates the utility of anatomical magnetic resonance imaging and semiautomated image analysis for detecting abnormal neuroarchitecture in mutant mice.
- Published
- 2006
33. Methods to rapidly and accurately screen a large number of ENU mutagenized mice for abnormal motor phenotypes
- Author
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Allison R Bechard, Steve J Clapcote, John C. Roder, Gang Xie, Daniel J. Kim, Tatiana V. Lipina, Wanda Abramow-Newerly, and Maria Abramow-Newerly
- Subjects
Male ,Positive control ,Mice, Transgenic ,Motor Activity ,Biology ,Body weight ,Motor function ,Andrology ,Mice ,Grip strength ,Superoxide Dismutase-1 ,Grip Strength Test ,Visual assessment ,Animals ,Postural Balance ,Genetics ,Movement Disorders ,Behavior, Animal ,Hand Strength ,Superoxide Dismutase ,Reproducibility of Results ,General Medicine ,Phenotype ,Mice, Inbred C57BL ,Neurology ,Ethylnitrosourea ,Neurology (clinical) ,Locomotion ,Mutagens ,Genetic screen - Abstract
In a dominant genetic screen for late-onset motor impairments in mice, 16-20-week-old N-nitroso-N-ethylurea (ENU)-mutagenized females were subjected to a behavioural test battery consisting of a visual assessment followed by the vertical pole, rotarod and grip strength tests. SOD1-G93A transgenic mice were tested in parallel as a positive control to provide information on the validity and sensitivity of the screen. From among the 1500 G1 ENU mice screened, four affected mice with impaired motor function were classified as outliers. Approximately 32% of the G2 and G3 progeny of one outlier were affected. Vertical pole, rotarod and grip strength test scores were significantly correlated with each other and with body weight in the G1 progeny, but the correlation with body weight was not maintained in the G2 and G3 progeny. We found that two tests, tail suspension and vertical pole, were sufficient to distinguish ENU outliers and SOD1-G93A hemizygotes from control mice, and could detect abnormalities earlier and more frequently than the other tests employed.
- Published
- 2006
34. Cognitive Deficits in Calsyntenin-2-deficient Mice Associated with Reduced GABAergic Transmission
- Author
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Nils Brose, Daisaku Yokomaku, Tatiana V. Lipina, John C. Roder, Ann Marie Craig, Lin Luo, Hiroshi Kawabe, Steven A. Connor, Yu Tian Wang, and Tuhina Prasad
- Subjects
0301 basic medicine ,Male ,Elevated plus maze ,Hippocampus ,Morris water navigation task ,Fluorescent Antibody Technique ,Motor Activity ,Synaptic Transmission ,Synapse ,Tissue Culture Techniques ,03 medical and health sciences ,Interneurons ,Animals ,Maze Learning ,gamma-Aminobutyric Acid ,Spatial Memory ,Pharmacology ,Mice, Knockout ,biology ,Calcium-Binding Proteins ,Brain ,Membrane Proteins ,Neural Inhibition ,Recognition, Psychology ,Associative learning ,Barnes maze ,Mice, Inbred C57BL ,Psychiatry and Mental health ,030104 developmental biology ,Parvalbumins ,biology.protein ,Excitatory postsynaptic potential ,Exploratory Behavior ,Female ,Original Article ,Psychology ,Cognition Disorders ,Neuroscience ,Parvalbumin - Abstract
Calsyntenin-2 has an evolutionarily conserved role in cognition. In a human genome-wide screen, the CLSTN2 locus was associated with verbal episodic memory, and expression of human calsyntenin-2 rescues the associative learning defect in orthologous Caenorhabditis elegans mutants. Other calsyntenins promote synapse development, calsyntenin-1 selectively of excitatory synapses and calsyntenin-3 of excitatory and inhibitory synapses. We found that targeted deletion of calsyntenin-2 in mice results in a selective reduction in functional inhibitory synapses. Reduced inhibitory transmission was associated with a selective reduction of parvalbumin interneurons in hippocampus and cortex. Clstn2(-/-) mice showed normal behavior in elevated plus maze, forced swim test, and novel object recognition assays. However, Clstn2(-/-) mice were hyperactive in the open field and showed deficits in spatial learning and memory in the Morris water maze and Barnes maze. These results confirm a function for calsyntenin-2 in cognitive performance and indicate an underlying mechanism that involves parvalbumin interneurons and aberrant inhibitory transmission.
- Published
- 2014
35. Modulators of the glycine site on NMDA receptors, d-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia
- Author
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John C. Roder, Viviane Labrie, Tatiana V. Lipina, and Ina Weiner
- Subjects
Male ,medicine.medical_specialty ,Psychosis ,Receptors, N-Methyl-D-Aspartate ,Glycine transporter ,Mice ,Latent inhibition ,Glycine Plasma Membrane Transport Proteins ,Internal medicine ,Conditioning, Psychological ,Serine ,medicine ,Animals ,Attention ,Clozapine ,Prepulse inhibition ,Pharmacology ,Chemistry ,Antagonist ,medicine.disease ,Mice, Inbred C57BL ,Dizocilpine ,Disease Models, Animal ,Amino Acid Transport Systems, Neutral ,Endocrinology ,Schizophrenia ,NMDA receptor ,Dizocilpine Maleate ,medicine.drug - Abstract
Schizophrenia is characterized by disturbances in sensorimotor gating and attentional processes, which can be measured by prepulse inhibition (PPI) and latent inhibition (LI), respectively. Research has implicated dysfunction of neurotransmission at the NMDA-type glutamate receptor in this disorder. This study was conducted to examine whether compounds that enhance NMDA receptor (NMDAR) activity via glycine B site, d-serine and ALX 5407 (glycine transporter type 1 inhibitor), alter PPI and LI in the presence or absence of an NMDAR antagonist, MK-801. C57BL/6J mice were tested in a standard PPI paradigm with three prepulse intensities. LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a noise in mice that previously received 0 (non-preexposed) or 40 noise exposures (preexposed) followed by two or four noise–foot shock pairings. Clozapine (3 mg/kg) and d-serine (600 mg/kg), but not ALX 5407, facilitated PPI. MK-801 dose dependently reduced PPI. The PPI disruptive effect of MK-801 (1 mg/kg) could be reversed by clozapine and ALX 5407, but not by d-serine. All the compounds were able to potentiate LI under conditions that disrupted LI in controls. MK-801 induced abnormal persistence of LI at a dose of 0.15 mg/kg. Clozapine, d-serine, and ALX 5407 were equally able to reverse persistent LI induced by MK-801. d-Serine and ALX 5407 display similar effects to clozapine in PPI and LI mouse models, suggesting potential neuroleptic action. Moreover, the finding that agonists of NMDARs and clozapine can restore disrupted LI and disrupt persistent LI may point to a unique ability of the NMDA system to regulate negative and positive symptoms of schizophrenia.
- Published
- 2005
36. Erratum: Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition
- Author
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Alexander McGirr, Tatiana V Lipina, Ho-Suk Mun, John Georgiou, Ahmed H Al-Amri, Enoch Ng, Dongxu Zhai, Christina Elliott, Ryan T Cameron, Jonathan GL Mullins, Fang Liu, George S Baillie, Steven J Clapcote, and John C Roder
- Subjects
Pharmacology ,0303 health sciences ,03 medical and health sciences ,Psychiatry and Mental health ,0302 clinical medicine ,030217 neurology & neurosurgery ,030304 developmental biology - Published
- 2017
37. α7nAchR/NMDAR coupling affects NMDAR function and object recognition
- Author
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Tatiana V. Lipina, John C. Roder, Fang Liu, Qiang Nai, and Shupeng Li
- Subjects
alpha7 Nicotinic Acetylcholine Receptor ,Long-Term Potentiation ,Hippocampus ,Morris water navigation task ,Hippocampal formation ,Receptors, N-Methyl-D-Aspartate ,Choline ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Memory ,mental disorders ,Learning ,Animals ,Rats, Wistar ,Molecular Biology ,Cells, Cultured ,Ion channel ,030304 developmental biology ,Neurons ,0303 health sciences ,Chemistry ,Research ,musculoskeletal, neural, and ocular physiology ,Excitatory Postsynaptic Potentials ,Recognition, Psychology ,Long-term potentiation ,Rats ,Up-Regulation ,NMDAR ,α7nAchR ,Electrophysiology ,nervous system ,Excitatory postsynaptic potential ,NMDA receptor ,LTP ,Peptides ,Ion Channel Gating ,Neuroscience ,psychological phenomena and processes ,030217 neurology & neurosurgery ,Protein Binding - Abstract
The α7 nicotinic acetylcholine receptor (nAchR) and NMDA glutamate receptor (NMDAR) are both ligand-gated ion channels permeable to Ca2+ and Na+. Previous studies have demonstrated functional modulation of NMDARs by nAchRs, although the molecular mechanism remains largely unknown. We have previously reported that α7nAchR forms a protein complex with the NMDAR through a protein-protein interaction. We also developed an interfering peptide that is able to disrupt the α7nAchR-NMDAR complex and blocks cue-induced reinstatement of nicotine-seeking in rat models of relapse. In the present study, we investigated whether the α7nAchR-NMDAR interaction is responsible for the functional modulation of NMDAR by α7nAchR using both electrophysiological and behavioral tests. We have found that activation of α7nAchR upregulates NMDAR-mediated whole cell currents and LTP of mEPSC in cultured hippocampal neurons, which can be abolished by the interfering peptide that disrupts the α7nAchR-NMDAR interaction. Moreover, administration of the interfering peptide in mice impairs novel object recognition but not Morris water maze performance. Our results suggest that α7nAchR/NMDAR coupling may selectively affect some aspects of learning and memory.
- Published
- 2013
38. [Untitled]
- Author
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Tatiana V. Lipina, N. P. Bondar, Natalia N. Kudryavtseva, Damira F. Avgustinovich, and Olga V. Alekseyenko
- Subjects
medicine.medical_specialty ,Male mice ,Open field ,Developmental psychology ,Familiar environment ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Trait ,Anxiety ,Home cage ,Trait anxiety ,Behavioral strategy ,medicine.symptom ,Psychology ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics - Abstract
The behaviors of male mice of the C57BL/6J (C57), CBA/Lac (CBA) and BALB/c (BALB) strains have been studied in the plus-maze and open field tests for estimation of state anxiety in the stressful novel conditions, and in the cubic box test (exploration of novel cubic box) and the partition test (behavioral reactivity to the unfamiliar partner in the neighboring compartment) for estimation of trait anxiety in the unstressful familiar conditions of the home cage. Plus-maze data suggest that C57 mice are the more anxious than CBA and BALB ones. However, it was revealed the opposite rank order in the open field. The study on the effect of pre-testing in the one of test on the behavior in the other test revealed active behavioral strategy in C57 mice in any situations. The plus-maze behavior of CBA mice was affected to a much lesser extent than in C57 ones after pre-testing in the open field, but expressed changes were observed in open field behavior of CBA mice after pre-testing in the plus-maze. BALB mice displayed low-reactive behavior after any pre-testing exposure under the state anxiety-provoking conditions. Familiar environment revealed a higher level of trait anxiety in C57 than males of other two strains: CBA and BALB mice willingly explore unfamiliar partner and cubic box while C57 mice avoid its. Mainly genetically inherent state anxiety in CBA mice and trait anxiety in C57 mice has been suggested. Lowest state and trait indices of anxiety were revealed in BALB mice in these conditions.
- Published
- 2000
39. Dual inhibitor of PDE7 and GSK-3 - VP1.15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice
- Author
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Carmen Gil, Ana Martínez, John C. Roder, Tatiana V. Lipina, and Valle Palomo
- Subjects
Male ,Phosphodiesterase Inhibitors ,medicine.medical_treatment ,Spatial Behavior ,Pharmacology ,Glycogen Synthase Kinase 3 ,Mice ,Cellular and Molecular Neuroscience ,DISC1 ,Latent inhibition ,Memory ,medicine ,Animals ,Molecular Targeted Therapy ,Enzyme Inhibitors ,Antipsychotic ,Amphetamine ,Episodic memory ,Nootropic Agents ,Cognitive deficit ,Cyclic Nucleotide Phosphodiesterases, Type 7 ,Behavior, Animal ,Dose-Response Relationship, Drug ,biology ,Working memory ,Neural Inhibition ,Drugs, Investigational ,Triazoles ,medicine.disease ,Mice, Inbred C57BL ,Schizophrenia ,Quinazolines ,biology.protein ,medicine.symptom ,Cognition Disorders ,Psychology ,Antipsychotic Agents ,medicine.drug - Abstract
Cognitive deficit is a core of schizophrenia and it is not effectively treated by the available antipsychotic drugs, hence new and more effective therapy is needed. Schizophrenia is considered as a pathway disorder where Disrupted-In-Schizophrenia-1 (DISC1) is important molecular player that regulates multiple cellular cascades. We recently reported synergistic action between phosphodiesterase-4 (PDE4) and glycogen synthase kinase-3 (GSK-3) as DISC1 interacting proteins. In the current study we characterized behavioural effects of a newly developed compound, VP1.15 that inhibits both PDE7 and GSK-3 with main focus on its antipsychotic and cognitive capacities. VP1.15 reduced ambulation in C57BL/6J mice in a dose-dependent manner (7.5 mg/kg and 3 mg/kg, respectively) and, hence, lower dose was chosen for the further analysis. VP1.1.5 facilitated pre-pulse inhibition (PPI), reversed amphetamine- but not MK-801-induced PPI deficit. The drug was able to ameliorate the disrupted latent inhibition (LI) induced by the increased number of conditioning trials and reversed amphetamine-induced LI deficit, supporting further its antipsychotic effects. The drug also significantly improved episodic memory in the spatial object recognition test, facilitated working memory in Y-maze and enhanced cued fear memory, but had no effect on executive function in the Puzzle box and contextual fear conditioning. Taken together, VP1.15 elicited antipsychotic effects and also facilitated cognitive domains in mice, suggesting that multitarget drugs, affecting molecular substrates from the same pathway, perhaps could be antipsychotics of new-generation that open a new possibilities in drug discoveries. This article is part of a Special Issue entitled 'Cognitive Enhancers'. © 2012 Elsevier Ltd. All rights reserved.
- Published
- 2013
40. Disrupted-In-Schizophrenia-1 Gln31Leu Polymorphism Results in Social Anhedonia Associated with Monoaminergic Imbalance and Reduction of CREB and β-arrestin-1,2 in the Nucleus Accumbens in a Mouse Model of Depression
- Author
-
Paul J. Fletcher, Tatiana V. Lipina, Albert H.C. Wong, Frankie H. F. Lee, and John C. Roder
- Subjects
Male ,Anhedonia ,Arrestins ,Glutamine ,Mice, Transgenic ,Nerve Tissue Proteins ,Nucleus accumbens ,CREB ,Nucleus Accumbens ,DISC1 ,Mice ,Leucine ,Desipramine ,Monoaminergic ,Genetic model ,medicine ,Animals ,Biogenic Monoamines ,Cyclic AMP Response Element-Binding Protein ,beta-Arrestins ,Pharmacology ,Polymorphism, Genetic ,biology ,Depression ,Antidepressive Agents ,Mice, Inbred C57BL ,Psychiatry and Mental health ,Disease Models, Animal ,beta-Arrestin 1 ,biology.protein ,Antidepressant ,Original Article ,medicine.symptom ,Psychology ,Neuroscience ,medicine.drug ,Signal Transduction - Abstract
Disrupted-in-schizophrenia-1 (DISC1) is associated with mental disorders, including major depression. We previously showed that DISC1-Q31L mutant mice have depression-like behaviors and can therefore be used to study neurobiological mechanisms of depression and antidepressant (AD) medication action. First, we found reduced levels of dopamine, serotonin and norepinephrine in the nucleus accumbens (NAC) of DISC1-Q31L mutants. Next, we assessed social-conditioned place preference as a reward-dependent task and the capacity of distinct ADs to correct impaired social behavior in DISC1-Q31L mice. Bupropion, but not fluoxetine or desipramine, was able to correct deficient social facilitation, social reward, and social novelty in DISC1-Q31L mutants, whereas all three ADs were able to improve social motivation and behavioral despair in DISC1-Q31L mutants. Furthermore, we sought to correlate social anhedonia with molecular and cellular features including dendritic spine density, β-arrestin-1,2, and cAMP-response-element-binding protein (CREB) in the NAC as biomarkers related to depression and the DISC1 pathway. DISC1-Q31L mutants showed reduced levels of β-arrestin-1,2, CREB, and spine density in the NAC, further supporting the construct validity of the genetic model. Bupropion induced the greatest effect on CREB in DISC1-Q31L mutants, whereas all studied ADs corrected the reduced levels of β-arrestin-1,2 and modestly ameliorated deficient spine density in this brain region. Overall, we find neurobiological changes accompanying social anhedonia in the NAC of DISC1-Q31L mutant mice, consistent with a role for DISC1 in regulating social reward as an endophenotype of depression.
- Published
- 2012
41. Prophylactic valproic acid treatment prevents schizophrenia-related behaviour in Disc1-L100P mutant mice
- Author
-
John C. Roder, Albert H.C. Wong, Tak W. Mak, Tatiana V. Lipina, Thorsten Berger, Paul C. Boutros, Fahmida Nipa Haque, Alexander McGirr, and Forloni, Gianluigi
- Subjects
Mouse ,lcsh:Medicine ,Social and Behavioral Sciences ,Hippocampus ,Mice ,0302 clinical medicine ,Latent inhibition ,Neurodevelopmental disorder ,Antimanic Agents ,Psychology ,2.1 Biological and endogenous factors ,Aetiology ,lcsh:Science ,Prepulse inhibition ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Psychiatry ,Oncogene Proteins ,0303 health sciences ,Valproic Acid ,Microscopy ,Multidisciplinary ,Microscopy, Confocal ,Behavior, Animal ,Homozygote ,Animal Models ,Lipocalins ,3. Good health ,Phenotype ,Mental Health ,Schizophrenia ,5.1 Pharmaceuticals ,Confocal ,Medicine ,Development of treatments and therapeutic interventions ,Neuroglia ,Locomotion ,medicine.drug ,Research Article ,medicine.medical_specialty ,Histology ,Clinical Research Design ,General Science & Technology ,Nerve Tissue Proteins ,Biology ,Crosses ,03 medical and health sciences ,DISC1 ,Model Organisms ,Genetic ,Lipocalin-2 ,Internal medicine ,Genetic model ,mental disorders ,Glial Fibrillary Acidic Protein ,medicine ,Genetics ,Animals ,Animal Models of Disease ,Crosses, Genetic ,030304 developmental biology ,Behavior ,Animal ,Gene Expression Profiling ,Prevention ,lcsh:R ,Human Genome ,medicine.disease ,Molecular biology ,Brain Disorders ,Endocrinology ,Gene Expression Regulation ,Developmental Psychology ,Mutation ,biology.protein ,RNA ,lcsh:Q ,030217 neurology & neurosurgery ,Gene Deletion ,Developmental Biology ,Neuroscience ,Acute-Phase Proteins - Abstract
Author(s): Lipina, Tatiana V; Haque, Fahmida Nipa; McGirr, Alexander; Boutros, Paul C; Berger, Thorsten; Mak, Tak W; Roder, John C; Wong, Albert HC | Abstract: BackgroundSchizophrenia is a neurodevelopmental disorder with onset early in adulthood. Disrupted-In-Schizophrenia-1 (DISC1) is a susceptibility gene for schizophrenia and other psychiatric disorders. Disc1-L100P mutant mice show behaviors relevant to schizophrenia at 12 weeks, but not at 8 weeks of age, and may be useful for investigating the onset of schizophrenia in early adulthood.MethodsWe investigated whether early valproic acid treatment would prevent behavioral, cellular and gene expression abnormalities in Disc1-L100P mutants.ResultsValproic acid prevented hyperactivity and deficits in prepulse inhibition and latent inhibition in Disc1-L100P mice. Genome-wide transcription profiling identified Lcn2 (lipocalin2) transcripts as being elevated by the Disc1 mutation and corrected by valproate. Disc1-L100P mice also had increased glial cell numbers in the subventricular zone, which was normalized by valproate. Genetic deletion of Lcn2 normalized glial cell numbers and behavior in Disc1-L100P mutants.ConclusionsPharmacological treatments are a feasible way of preventing abnormal behaviour in a genetic model of schizophrenia. Lcn2 is a potential novel drug target for early intervention in schizophrenia.
- Published
- 2012
42. GENETIC AND PHARMACOLOGICAL EVIDENCE FOR SCHIZOPHRENIA-RELATED DISC1 INTERACTION WITH GSK-3
- Author
-
James R. Woodgett, Oksana Kaidanovich-Beilin, Satish Patel, John C. Roder, Fang Liu, Tatiana V. Lipina, Steven J. Clapcote, and Min Wang
- Subjects
Male ,Mutant ,Blotting, Western ,Mutation, Missense ,Nerve Tissue Proteins ,medicine.disease_cause ,behavioral disciplines and activities ,Article ,Cellular and Molecular Neuroscience ,DISC1 ,Glycogen Synthase Kinase 3 ,Mice ,GSK-3 ,mental disorders ,medicine ,Missense mutation ,Animals ,Immunoprecipitation ,Glycogen synthase ,Protein kinase A ,Prepulse inhibition ,Genetics ,Mutation ,biology ,Behavior, Animal ,Gene Expression Profiling ,Mice, Mutant Strains ,Mice, Inbred C57BL ,Gene Expression Regulation ,biology.protein ,Schizophrenia - Abstract
Recent studies have identified disrupted-in-schizophrenia-1 (DISC1) as a strong genetic risk factor associated with schizophrenia. Previously, we have reported that a mutation in the second exon of the DISC1 gene [leucine to proline at amino acid position 100, L100P] leads to the development of schizophrenia-related behaviors in mice. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase that interacts with the N-terminal region of DISC1 (aa 1-220) and has been implicated as an important downstream component in the etiology of schizophrenia. Here, for the first time, we show that pharmacological and genetic inactivation of GSK-3 reverse prepulse inhibition and latent inhibition deficits as well as normalizing the hyperactivity of Disc1-L100P mutants. In parallel to these observations, interaction between DISC1 and GSK-3α and β is reduced in Disc1-L100P mutants. Our data provide genetic, biochemical, and behavioral evidence for a molecular link between DISC1 and GSK-3 in relation to psychopathology and highlights the value of missense mutations in dissecting the underlying and complex molecular mechanisms of neurological disorders.
- Published
- 2011
43. Assessment of Social Interaction Behaviors
- Author
-
Igor Vukobradovic, Tatiana V. Lipina, John C. Roder, Oksana Kaidanovich-Beilin, and James R. Woodgett
- Subjects
phenotyping ,General Chemical Engineering ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,behavioral test ,Social Behavior ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Behavior, Animal ,General Immunology and Microbiology ,Issue 48 ,General Neuroscience ,Novelty ,social interaction ,medicine.disease ,Social relation ,Preference ,Test (assessment) ,Behavioral test ,Mate choice ,Schizophrenia ,Autism ,Psychology ,030217 neurology & neurosurgery ,Neuroscience ,Behavioral Research ,Cognitive psychology - Abstract
Social interactions are a fundamental and adaptive component of the biology of numerous species. Social recognition is critical for the structure and stability of the networks and relationships that define societies. For animals, such as mice, recognition of conspecifics may be important for maintaining social hierarchy and for mate choice 1. A variety of neuropsychiatric disorders are characterized by disruptions in social behavior and social recognition, including depression, autism spectrum disorders, bipolar disorders, obsessive-compulsive disorders, and schizophrenia. Studies of humans as well as animal models (e.g., Drosophila melanogaster, Caenorhabditis elegans, Mus musculus, Rattus norvegicus) have identified genes involved in the regulation of social behavior 2. To assess sociability in animal models, several behavioral tests have been developed (reviewed in 3). Integrative research using animal models and appropriate tests for social behavior may lead to the development of improved treatments for social psychopathologies. The three-chamber paradigm test known as Crawley's sociability and preference for social novelty protocol has been successfully employed to study social affiliation and social memory in several inbred and mutant mouse lines (e.g. 4-7). The main principle of this test is based on the free choice by a subject mouse to spend time in any of three box's compartments during two experimental sessions, including indirect contact with one or two mice with which it is unfamiliar. To quantitate social tendencies of the experimental mouse, the main tasks are to measure a) the time spent with a novel conspecific and b) preference for a novel vs. a familiar conspecific. Thus, the experimental design of this test allows evaluation of two critical but distinguishable aspects of social behavior, such as social affiliation/motivation, as well as social memory and novelty. "Sociability" in this case is defined as propensity to spend time with another mouse, as compared to time spent alone in an identical but empty chamber 7. "Preference for social novelty" is defined as propensity to spend time with a previously unencountered mouse rather than with a familiar mouse 7. This test provides robust results, which then must be carefully analyzed, interpreted and supported/confirmed by alternative sociability tests. In addition to specific applications, Crawley's sociability test can be included as an important component of general behavioral screen of mutant mice.
- Published
- 2011
44. Enhanced dopamine function in DISC1-L100P mutant mice: implications for schizophrenia
- Author
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Tatiana V. Lipina, Akira Sawa, Hanna Jaaro-Peled, Philip Seeman, Minae Niwa, John C. Roder, and Paul J. Fletcher
- Subjects
Male ,medicine.medical_specialty ,Reflex, Startle ,Dopamine ,Microdialysis ,Nerve Tissue Proteins ,Striatum ,Motor Activity ,Behavioral Neuroscience ,DISC1 ,Mice ,Latent inhibition ,Dopamine Uptake Inhibitors ,Dopamine receptor D2 ,Internal medicine ,Genetics ,medicine ,Haloperidol ,Animals ,Biogenic Monoamines ,Amphetamine ,Prepulse inhibition ,Chromatography, High Pressure Liquid ,Brain Chemistry ,biology ,Behavior, Animal ,Receptors, Dopamine D2 ,Sensory Gating ,Corpus Striatum ,Endocrinology ,Neurology ,Acoustic Stimulation ,Mutation ,biology.protein ,Schizophrenia ,Dopamine Antagonists ,Schizophrenic Psychology ,Psychology ,Neuroscience ,medicine.drug - Abstract
Significant advances have been made in understanding the role of disrupted-in-schizophrenia-1 (DISC1) in the brain and accumulating findings suggest the possible implication of DISC1 in the regulation of dopamine (DA) function. A mutation in the second exon of DISC1 at L100P leads to the development of schizophrenia-related behavior in mutant mice (DISC1-L100P). We investigated here the role of DA in the expression of schizophrenia-related endophenotypes in the DISC1-L100P genetic mouse model. The mutated DISC1 resulted in facilitation of the psychostimulant effect of amphetamine in DISC1-L100P mutant mice assessed in the open field and prepulse inhibition (PPI) tests. Biochemical studies detected a 2.1-fold increase in the proportion of striatal D receptors without significant changes in DA release in vivo in the striatum of DISC1-L100P mutants in response to the low dose of amphetamine. The D(2) receptor antagonist haloperidol reversed the hyperactivity, PPI and latent inhibition (LI) deficits and blocked the psychostimulant effect of amphetamine in DISC1-L100P mutants. Taken together, our findings show the role of DISC1 in D(2) -related pathophysiological mechanism of schizophrenia, linking DISC1 with well-established DA hypothesis of schizophrenia.
- Published
- 2010
45. Abnormalities in brain structure and behavior in GSK-3alpha mutant mice
- Author
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Oksana Kaidanovich-Beilin, Mustafa Khan, James R. Woodgett, Paul J. Fletcher, R. Mark Henkelman, John C. Roder, Tatiana V. Lipina, Matthijs C. van Eede, Tsuyoshi Miyakawa, Kenichi Okamoto, John W. Chambers, Satoko Hattori, Christine L. Laliberté, Keizo Takao, Katrina MacAulay, and Bradley W. Doble
- Subjects
Memory, Long-Term ,Emotions ,Mutant ,macromolecular substances ,Biology ,lcsh:RC346-429 ,Serine ,Glycogen Synthase Kinase 3 ,Mice ,Mice, Neurologic Mutants ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Neurochemical ,GSK-3 ,Animals ,Threonine ,Social Behavior ,Glycogen synthase ,Protein kinase A ,Gene ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,030304 developmental biology ,Mice, Knockout ,Neurotransmitter Agents ,0303 health sciences ,Behavior, Animal ,Depression ,Research ,Brain ,Magnetic Resonance Imaging ,Cell biology ,Aggression ,Mice, Inbred C57BL ,biology.protein ,Female ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Background Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by two genes that generate two related proteins: GSK-3α and GSK-3β. Mice lacking a functional GSK-3α gene were engineered in our laboratory; they are viable and display insulin sensitivity. In this study, we have characterized brain functions of GSK-3α KO mice by using a well-established battery of behavioral tests together with neurochemical and neuroanatomical analysis. Results Similar to the previously described behaviours of GSK-3β+/-mice, GSK-3α mutants display decreased exploratory activity, decreased immobility time and reduced aggressive behavior. However, genetic inactivation of the GSK-3α gene was associated with: decreased locomotion and impaired motor coordination, increased grooming activity, loss of social motivation and novelty; enhanced sensorimotor gating and impaired associated memory and coordination. GSK-3α KO mice exhibited a deficit in fear conditioning, however memory formation as assessed by a passive avoidance test was normal, suggesting that the animals are sensitized for active avoidance of a highly aversive stimulus in the fear-conditioning paradigm. Changes in cerebellar structure and function were observed in mutant mice along with a significant decrease of the number and size of Purkinje cells. Conclusion Taken together, these data support a role for the GSK-3α gene in CNS functioning and possible involvement in the development of psychiatric disorders.
- Published
- 2009
46. A new model of the disrupted latent inhibition in C57BL/6J mice after bupropion treatment
- Author
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Tatiana V. Lipina and John C. Roder
- Subjects
Male ,Psychosis ,Neurotransmission ,Pharmacology ,Piperazines ,Mice ,Latent inhibition ,Dopamine Uptake Inhibitors ,Conditioning, Psychological ,medicine ,Animals ,Drug Interactions ,Amphetamine ,Bupropion ,Clozapine ,Rolipram ,business.industry ,Dopaminergic ,food and beverages ,Neural Inhibition ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Inhibition, Psychological ,Schizophrenia ,Dopamine Agonists ,Haloperidol ,Schizophrenic Psychology ,Phosphodiesterase 4 Inhibitors ,business ,medicine.drug - Abstract
Schizophrenia is characterized by disturbances in attention and information processing that can be measured by latent inhibition (LI). Research has implicated significant aberrations in dopaminergic (DA) neurotransmission in this disorder.The objectives of this study were as follows: to probe whether bupropion disrupts LI; to compare its efficacy to the effects of GBR12783 (specific DA uptake inhibitor) and to amphetamine (DA releaser); to test if antipsychotics would reverse LI deficits induced by bupropion, GBR12783, and amphetamine; and to probe if rolipram (phosphodiesterase-4 inhibitor), which increases cyclic AMP (cAMP) similarly to antipsychotics, effectively corrects drug-induced LI deficits. Based on its efficacy in drug addiction, we also asked if bupropion could block the effect of amphetamine.LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a noise in C57BL/6J mice. Mice previously received 0 (nonpreexposed) or 40 noise exposures (preexposed) followed by two or four noise-foot shock pairings.Bupropion abolished LI in mice, which was corrected by rolipram, but not by haloperidol and clozapine. GBR12783 and amphetamine, but not antidepressants, also disrupted LI, and this was reversed by antipsychotics and rolipram. Both bupropion and amphetamine disrupted LI via conditioning session. Paradoxically, bupropion and GBR12783 also blocked the amphetamine-induced LI deficit.Efficacy of rolipram but not antipsychotics to reverse the effects of bupropion suggests novel cAMP-dependent and D(2) receptor-independent mechanisms of the bupropion-induced LI deficit. Further detailed biochemical analysis of bupropion-induced LI deficit might be a fruitful approach in developing new antipsychotics.
- Published
- 2009
47. Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning
- Author
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Daisy Joo, Colin McKerlie, David Ng, Miguel A. Cortez, Marijana Kanisek, Andréa Sertié, Rachel K. Szilard, Graham M. Pitcher, John C. Roder, Tatiana V. Lipina, Lorraine V. Kalia, Michael W. Salter, Steven J. Clapcote, and Roderick R. McInnes
- Subjects
Male ,QH301-705.5 ,Long-Term Potentiation ,Nonsynaptic plasticity ,Dioxoles ,Biology ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,Synaptic Transmission ,Neurological Disorders ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Piperidines ,Memory ,Metaplasticity ,LTP induction ,Animals ,Humans ,Learning ,Biology (General) ,LDL-Receptor Related Proteins ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Neuronal Plasticity ,General Immunology and Microbiology ,General Neuroscience ,musculoskeletal, neural, and ocular physiology ,Membrane Proteins ,Long-term potentiation ,Genetics and Genomics ,3. Good health ,Lipoproteins, LDL ,Mice, Inbred C57BL ,Biochemistry ,nervous system ,Synaptic plasticity ,Excitatory postsynaptic potential ,NMDA receptor ,General Agricultural and Biological Sciences ,Postsynaptic density ,Neuroscience ,030217 neurology & neurosurgery ,Research Article - Abstract
The N-methyl-D-aspartate receptor (NMDAR), a major excitatory ligand-gated ion channel in the central nervous system (CNS), is a principal mediator of synaptic plasticity. Here we report that neuropilin tolloid-like 1 (Neto1), a complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing transmembrane protein, is a novel component of the NMDAR complex critical for maintaining the abundance of NR2A-containing NMDARs in the postsynaptic density. Neto1-null mice have depressed long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, with the subunit dependency of LTP induction switching from the normal predominance of NR2A- to NR2B-NMDARs. NMDAR-dependent spatial learning and memory is depressed in Neto1-null mice, indicating that Neto1 regulates NMDA receptor-dependent synaptic plasticity and cognition. Remarkably, we also found that the deficits in LTP, learning, and memory in Neto1-null mice were rescued by the ampakine CX546 at doses without effect in wild-type. Together, our results establish the principle that auxiliary proteins are required for the normal abundance of NMDAR subunits at synapses, and demonstrate that an inherited learning defect can be rescued pharmacologically, a finding with therapeutic implications for humans., Author Summary The fundamental unit for information processing in the brain is the synapse, a highly specialized site of communication between the brain's multitude of individual neurons. The strength of the communication at each synapse changes in response to neuronal activity—a process called synaptic plasticity—allowing networks of neurons to adapt and learn. How synaptic plasticity occurs is a major question in neurobiology. A central player in synaptic plasticity is an assembly of synaptic proteins called the NMDA receptor complex. Here, we discovered that the protein Neto1 is a component of the NMDA receptor complex. Neto1-deficient mice had a dramatic decrease in the number of NMDA receptors at synapses and consequently, synaptic plasticity and learning were impaired. By indirectly enhancing the function of the residual NMDA receptors in Neto1-deficient mice with a small molecule, we restored synaptic plasticity and learning to normal levels. Our findings establish the principle that inherited abnormalities of synaptic plasticity and learning due to NMDA receptor dysfunction can be pharmacologically corrected. Our discoveries also suggest that synaptic proteins that share a molecular signature, called the CUB domain, with Neto1 may be important components of synaptic receptors across species, because several CUB-domain proteins in worms have also been found to regulate synaptic receptors., Spatial learning and memory depend on the N-methyl-D-aspartic acid receptor, a synaptic ion channel regulated by Neto1. Impaired cognition due to the absence of Neto1 can be rescued pharmacologically, a finding with implications for the therapy of inherited learning defects in humans.
- Published
- 2008
48. Beta N-acetylglucosaminyltransferase V (Mgat5) deficiency reduces the depression-like phenotype in mice
- Author
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L. Soleimani, John C. Roder, Tatiana V. Lipina, and James W. Dennis
- Subjects
medicine.medical_specialty ,Glycosylation ,Glycoconjugate ,Central nervous system ,Emotions ,Motor Activity ,N-Acetylglucosaminyltransferases ,Behavioral Neuroscience ,chemistry.chemical_compound ,Mice ,Polysaccharides ,Internal medicine ,Genetics ,medicine ,Reaction Time ,Animals ,Receptor ,Maze Learning ,Swimming ,Glycoproteins ,chemistry.chemical_classification ,Mice, Knockout ,Behavior, Animal ,Depression ,Neural tube ,Tail suspension test ,Antidepressive Agents ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Endocrinology ,Neurology ,chemistry ,Immunology ,Glycoprotein ,Stress, Psychological ,Behavioural despair test - Abstract
The central nervous system (CNS) is rich in glycoconjugates, located on cell surface and in extracellular matrix. The products of Golgi UDP-GlcNAc:N-acetylglucosaminyltransferases (encoded by Mgat1, Mgat2, Mgat4 and Mgat5) act sequentially to generate the GlcNAc-branched complex-type N-glycans on glycoprotein receptors. While elimination of all the branched N-glycans in Mgat1(-/-) mouse embryos is lethal at neural tube fold stage, decreased branching is associated with late developmental defects similar to type 2 of congenital disorders of glycosylation, with developmental and psychomotor abnormalities. To study the role of complex-type N-glycans in brain function, we tested Mgat5(-/-) mice in a battery of neurological and behavioral tests. Despite the absence of tri- and tetra-antennary products, Mgat5(-/-) mice were not different from their wild-type littermates in physical and neurological assessments, anxiety level, startle reactivity and sensorimotor gating. However, they displayed a robust decrease in the immobility time in the forced swim test and the tail suspension test independent of locomotor activity, interpreted as a change in depression-like behavior. This effect was accentuated after chronic mild stress. Comparable increase in plasma corticosterone of Mgat5(+/+) and Mgat5(-/-) mice in response to acute stress shows an intact function of the hypothalamus-pituitary-adrenal axis. A change in social interactions was also observed. Our results indicate that Mgat5 modification of complex-type N-glycans on CNS glycoproteins is involved in the regulation of depression-like behavior.
- Published
- 2007
49. Self-directed exploration provides a Ncs1-dependent learning bonus
- Author
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Tatiana V. Lipina, Yoichi Gondo, Enoch Ng, Ho Suk Mun, John C. Roder, Alexander McGirr, Bechara J. Saab, and John Georgiou
- Subjects
Male ,Neuronal Calcium-Sensor Proteins ,education ,Hippocampus ,Environment ,Hippocampal formation ,Nucleus accumbens ,Nucleus Accumbens ,Article ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Learning ,Premovement neuronal activity ,Spatial Memory ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,biology ,Receptors, Dopamine D2 ,Dentate gyrus ,Repertoire ,Neuropeptides ,Cognition ,CA3 Region, Hippocampal ,Mice, Inbred C57BL ,Neuronal calcium sensor-1 ,Gene Knockdown Techniques ,Dentate Gyrus ,Exploratory Behavior ,biology.protein ,Psychology ,Proto-Oncogene Proteins c-fos ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Understanding the mechanisms of memory formation is fundamental to establishing optimal educational practices and restoring cognitive function in brain disease. Here, we show for the first time in a non-primate species, that spatial learning receives a special bonus from self-directed exploration. In contrast, when exploration is escape-oriented, or when the full repertoire of exploratory behaviors is reduced, no learning bonus occurs. These findings permitted the first molecular and cellular examinations into the coupling of exploration to learning. We found elevated expression of neuronal calcium sensor 1 (Ncs1) and dopamine type-2 receptors upon self-directed exploration, in concert with increased neuronal activity in the hippocampal dentate gyrus and area CA3, as well as the nucleus accumbens. We probed further into the learning bonus by developing a point mutant mouse (Ncs1P144S/P144S) harboring a destabilized NCS-1 protein and found this line lacked the equivalent self-directed exploration learning bonus. Acute knock-down of Ncs1 in the hippocampus also decoupled exploration from efficient learning. These results are potentially relevant for augmenting learning and memory in health and disease and provide the basis for further molecular and circuit analyses in this direction.
- Published
- 2015
50. Effects of haloperidol on communicative and aggressive behavior in male mice with different experiences of aggression
- Author
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Natalia N. Kudryavtseva, Tatiana V Lipina, and Ludmila A Koryakina
- Subjects
Male ,medicine.medical_specialty ,Clinical Biochemistry ,Male mice ,Toxicology ,Affect (psychology) ,Biochemistry ,Developmental psychology ,Behavioral Neuroscience ,Mice ,Internal medicine ,medicine ,Haloperidol ,Animals ,Latency (engineering) ,Biological Psychiatry ,Pharmacology ,Behavior, Animal ,Dose-Response Relationship, Drug ,Aggression ,Antagonist ,Dopamine antagonist ,Animal Communication ,Mice, Inbred C57BL ,Endocrinology ,Dopamine receptor ,Dopamine Antagonists ,medicine.symptom ,Psychology ,medicine.drug - Abstract
Effects of two doses of haloperidol (0.1 and 0.4 mg/kg, 30 min and 24 h, IP) on communicative and aggressive behavior in C57BL/6J male mice have been studied. Some of the mice were without prior experience of aggression (“recruits”); the others had been victorious in 20 daily aggressive confrontations (“experienced winners”). Communicative behavior was estimated as the behavioral reaction to a standard tester (loser) in the partition test. Haloperidol in either dose significantly reduced communicative behavior in the “recruits,” but not in the “experienced winners.” Significantly fewer attacks, less total attacking time, and total time of aggressive behavior (aggressive grooming + attacks) were demonstrated by the “experiences winners,” than by the “recruits,” while the latency of the first attack, the number, the total and average duration of aggressive grooming events were significantly higher. In the “recruits,” haloperidol dose dependently increased the latency and decreased the number of attacks, the total attacking time, and the total time of aggressive behavior 30 min and 24 h after injection. However, haloperidol did not affect the average or total time of aggressive grooming. Neither dose significantly affected any measure of aggressive behavior in the “experienced winners.” It has been concluded that repeated aggression experience reduces the pharmacological sensitivity of the dopamine receptors.
- Published
- 1999
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