37 results on '"Gilabert-Juan J"'
Search Results
2. Impact of stress on inhibitory neuronal circuits, our tribute to Bruce McEwen
- Author
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Perez-Rando M, Carceller H, Castillo-Gomez E, Bueno-Fernandez C, Garcia-Mompo C, Gilabert-Juan J, Guirado R, Pesarico A, and Nacher J
- Abstract
This manuscript is dedicated to the memory of Bruce S. McEwen, to commemorate the impact he had on how we understand stress and neuronal plasticity, and the profound influence he exerted on our scientific careers. The focus of this review is the impact of stressors on inhibitory circuits, particularly those of the limbic system, but we also consider other regions affected by these adverse experiences. We revise the effects of acute and chronic stress during different stages of development and lifespan, taking into account the influence of the sex of the animals. We review first the influence of stress on the physiology of inhibitory neurons and on the expression of molecules related directly to GABAergic neurotransmission, and then focus on specific interneuron subpopulations, particularly on parvalbumin and somatostatin expressing cells. Then we analyze the effects of stress on molecules and structures related to the plasticity of inhibitory neurons: the polysialylated form of the neural cell adhesion molecule and perineuronal nets. Finally, we review the potential of antidepressants or environmental manipulations to revert the effects of stress on inhibitory circuits. © 2022 The Authors.
- Published
- 2022
3. FOXP2 expression and gray matter density in the male brains of patients with schizophrenia
- Author
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Sanjuán J, Castro-Martinez X, García-Martí G, González-Fernández J, Sanz-Requena R, Haro JM, Meana JJ, Martí-Bonmatí L, Nacher J, Sebastiá-Ortega N, Gilabert-Juan J, and Moltó MD
- Subjects
Male ,Magnetic resonance imaging ,FOXP2 ,Schizophrenia ,Gray matter - Abstract
Common genetic variants of FOXP2 may contribute to schizophrenia vulnerability, but controversial results have been reported for this proposal. Here we evaluated the potential impact of the common FOXP2 rs2396753 polymorphism in schizophrenia. It was previously reported to be part of a risk haplotype for this disease and to have significant effects on gray matter concentration in the patients. We undertook the first examination into whether rs2396753 affects the brain expression of FOXP2 and a replication study of earlier neuroimaging findings of the influence of this genetic variant on brain structure. FOXP2 expression levels were measured in postmortem prefrontal cortex samples of 84 male subjects (48 patients and 36 controls) from the CIBERSAM Brain and the Stanley Foundation Array Collections. High-resolution anatomical magnetic resonance imaging was performed on 79 male subjects (61 patients, 18 controls) using optimized voxel-based morphometry. We found differences in FOXP2 expression and brain morphometry depending on the rs2396753, relating low FOXP2 mRNA levels with reduction of gray matter density. We detected an interaction between rs2396753 and the clinical groups, showing that heterozygous patients for this polymorphism have gray matter density decrease and low FOXP2 expression comparing with the heterozygous controls. This study shows the importance of independent replication of neuroimaging genetic studies of FOXP2 as a candidate gene in schizophrenia. Furthermore, our results suggest that the FOXP2 rs2396753 affects mRNA levels, thus providing new knowledge about its significance as a potential susceptibility polymorphism in schizophrenia.
- Published
- 2021
4. Delta-9-Tetrahydrocannabinol treatment during adolescence and alterations in the inhibitory networks of the adult prefrontal cortex in mice subjected to perinatal NMDA receptor antagonist injection and to postweaning social isolation
- Author
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Garcia-Mompo C, Curto Y, Carceller H, Gilabert-Juan J, Rodriguez-Flores E, Guirado R, and Nacher J
- Subjects
nervous system - Abstract
The prefrontal cortex (PFC) continues its development during adolescence and alterations in its structure and function, particularly of inhibitory networks, have been detected in schizophrenic patients. Since cannabis use during adolescence is a risk factor for this disease, our main objective was to investigate whether THC administration during this period might exacerbate alterations in prefrontocortical inhibitory networks in mice subjected to a perinatal injection of MK801 and postweaning social isolation. This double-hit model (DHM) combines a neurodevelopmental manipulation and the exposure to an aversive experience during early life; previous work has shown that DHM mice have important alterations in the structure and connectivity of PFC interneurons. In the present study we found that DHM had reductions in prepulse inhibition of the startle reflex (PPI), GAD67 expression and cingulate 1 cortex volume. Interestingly, THC by itself induced increases in PPI and decreases in the dendritic complexity of somatostatin expressing interneurons. Both THC and DHM reduced the density of parvalbumin expressing cells surrounded by perineuronal nets and, when combined, they disrupted the ratio between the density of puncta expressing excitatory and inhibitory markers. Our results support previous work showing alterations in parameters involving interneurons in similar animal models and schizophrenic patients. THC treatment does not modify further these parameters, but changes some others related also to interneurons and their plasticity, in some cases in the opposite direction to those induced by the DHM, suggesting a protective effect.
- Published
- 2020
5. Time dependent expression of the blood biomarkers eif2d and tox in patients with schizophrenia
- Author
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Gilabert-Juan J, Lopez-Campos G, Sebastia-Ortega N, Guara-Ciurana S, Ruso-Julve F, Prieto C, Crespo-Facorro B, Sanjuan J, and Molto M
- Published
- 2019
6. Morphological alterations in the hippocampus of the Ts65Dn mouse model for Down syndrome correlate with structural plasticity markers
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Villarroya O, Ballestin R, Lopez-Hidalgo R, Mulet M, Blasco-Ibanez J, Crespo C, Nacher J, Gilabert-Juan J, and Varea E
- Published
- 2018
7. Non-cell autonomous OTX2 transcription factor regulates anxiety-related behavior in the mouse
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Vincent, C., primary, Gilabert-Juan, J., additional, Gibel-Russo, R., additional, Alvarez-Fischer, D., additional, Krebs, M.-O., additional, Le Pen, G., additional, Prochiantz, A., additional, and Di Nardo, A.A., additional
- Published
- 2019
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8. Early Social Isolation Stress and Perinatal NMDA Receptor Antagonist Treatment Induce Changes in the Structure and Neurochemistry of Inhibitory Neurons of the Adult Amygdala and Prefrontal Cortex
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Castillo-Gomez E, Perez-Rando M, Belles M, Gilabert-Juan J, Llorens J, Carceller H, Bueno-Fernandez C, Garcia-Mompo C, Ripoll-Martinez B, Curto Y, Sebastia-Ortega N, Molto M, Sanjuan J, and Nacher J
- Published
- 2017
9. Reduced interneuronal dendritic arborization in CA1 but not in CA3 region of mice subjected to chronic mild stress
- Author
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Gilabert-Juan J, Bueno-Fernandez C, Castillo-Gomez E, and Nacher J
- Published
- 2017
10. Hypocellularity in the Murine Model for Down Syndrome Ts65Dn Is Not Affected by Adult Neurogenesis
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Lopez-Hidalgo R, Ballestin R, Vega J, Blasco-Ibanez J, Crespo C, Gilabert-Juan J, Nacher J, and Varea E
- Published
- 2016
11. Gene expression biomarkers related to auditory hallucinations in peripheral blood of patients with schizophrenia
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Gilabert-Juan, J., primary, Lopez-Campos, G., additional, Sebastia-Ortega, N., additional, Guara, S., additional, Sanjuan, J., additional, and Molto, M.D., additional
- Published
- 2017
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12. Semaphorin and plexin gene expression is altered in the prefrontal cortex of schizophrenia patients with and without auditory hallucinations
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Gilabert-Juan J, Sáez AR, Lopez-Campos G, Sebastiá-Ortega N, González-Martínez R, Costa J, Haro JM, Callado LF, Meana JJ, Nacher J, Sanjuán J, and Moltó MD
- Subjects
body regions ,Auditory hallucinations, Gene expression, Plexins, Prefrontal cortex, Schizophrenia, Semaphorins - Abstract
Auditory hallucinations (AH) are clinical hallmarks of schizophrenia, however little is known about molecular genetics of these symptoms. In this study, gene expression profiling of postmortem brain samples from prefrontal cortex of schizophrenic patients without AH (SNA), patients with AH (SA) and control subjects were compared. Genome-wide expression analysis was conducted using samples of three individuals of each group and the Affymetrix GeneChip Human-Gene 1.0 ST-Array. This analysis identified the Axon Guidance pathway as one of the most differentially expressed network among SNA, SA and CNT. To confirm the transcriptome results, mRNA level quantification of seventeen genes involved in this pathway was performed in a larger sample. PLXNB1, SEMA3A, SEMA4D and SEM6C were upregulated in SNA or SA patients compared to controls. PLXNA1 and SEMA3D showed down-regulation in their expression in the patient's samples, but differences remained statistically significant between the SNA patients and controls. Differences between SNA and SA were found in PLXNB1 expression which is decreased in SA patients. This study strengthens the contribution of brain plasticity in pathophysiology of schizophrenia and shows that non-hallucinatory patients present more alterations in frontal regions than patients with hallucinations concerning neural plasticity.
- Published
- 2015
13. P.1.a.007 - Gene expression biomarkers related to auditory hallucinations in peripheral blood of patients with schizophrenia
- Author
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Gilabert-Juan, J., Lopez-Campos, G., Sebastia-Ortega, N., Guara, S., Sanjuan, J., and Molto, M.D.
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- 2017
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14. P.3.b.002 A dual rat model of schizophrenia reveals deficiencies in the gene and protein expression at the medial prefrontal cortex and amygdala
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Gilabert-Juan, J., primary, Saez, A.R., additional, Carceller, H., additional, Belles, M., additional, Molto, M.D., additional, and Nacher, J., additional
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- 2012
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15. P.2.h.002 Chronic stress induces changes in neuronal plasticity and inhibitory neurotransmission in the amygdala of adult mice
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Gilabert-Juan, J., primary, Castillo-Gomez, E., additional, Moltó, M.D., additional, and Nàcher, J., additional
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- 2010
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16. Genética del temperamento en niños
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Ivorra Martínez, J.L., primary, Gilabert Juan, J., additional, Moltó Ruiz, María Dolores, additional, and Sanjuán Arias, Julio, additional
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- 2007
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17. The genetics of child temperament,Genética del temperamento en niños
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Ivorra-Martínez, J., Gilabert-Juan, J., Maria Dolores Molto, and Sanjuán, J.
18. Genetic interaction between PLK1 and downstream MCPH proteins in the control of centrosome asymmetry and cell fate during neural progenitor division.
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González-Martínez J, Cwetsch AW, Gilabert-Juan J, Gómez J, Garaulet G, Schneider P, de Cárcer G, Mulero F, Caleiras E, Megías D, Porlan E, and Malumbres M
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- Cell Differentiation, Centrosome metabolism, Child, Chromosome Segregation, Humans, Mutation genetics, Nerve Tissue Proteins metabolism, Polo-Like Kinase 1, Cell Cycle Proteins genetics, Microcephaly genetics, Microcephaly metabolism, Neural Stem Cells cytology, Protein Serine-Threonine Kinases genetics, Proto-Oncogene Proteins genetics
- Abstract
Alteration of centrosome function and dynamics results in major defects during chromosome segregation and is associated with primary autosomal microcephaly (MCPH). Despite the knowledge accumulated in the last few years, why some centrosomal defects specifically affect neural progenitors is not clear. We describe here that the centrosomal kinase PLK1 controls centrosome asymmetry and cell fate in neural progenitors during development. Gain- or loss-of-function mutations in Plk1, as well as deficiencies in the MCPH genes Cdk5rap2 (MCPH3) and Cep135 (MCPH8), lead to abnormal asymmetry in the centrosomes carrying the mother and daughter centriole in neural progenitors. However, whereas loss of MCPH proteins leads to increased centrosome asymmetry and microcephaly, deficient PLK1 activity results in reduced asymmetry and increased expansion of neural progenitors and cortical growth during mid-gestation. The combination of PLK1 and MCPH mutations results in increased microcephaly accompanied by more aggressive centrosomal and mitotic abnormalities. In addition to highlighting the delicate balance in the level and activity of centrosomal regulators, these data suggest that human PLK1, which maps to 16p12.1, may contribute to the neurodevelopmental defects associated with 16p11.2-p12.2 microdeletions and microduplications in children with developmental delay and dysmorphic features., (© 2022. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)
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- 2022
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19. Non-cell-autonomous OTX2 transcription factor regulates anxiety-related behavior in the mouse.
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Vincent C, Gilabert-Juan J, Gibel-Russo R, Alvarez-Fischer D, Krebs MO, Le Pen G, Prochiantz A, and Di Nardo AA
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- Animals, Anxiety, Female, Interneurons metabolism, Male, Mice, Parvalbumins metabolism, Choroid Plexus metabolism, Otx Transcription Factors genetics, Otx Transcription Factors metabolism
- Abstract
The OTX2 homeoprotein transcription factor is expressed in the dopaminergic neurons of the ventral tegmental area, which projects to limbic structures controlling complex behaviors. OTX2 is also produced in choroid plexus epithelium, from which it is secreted into cerebrospinal fluid and transferred to limbic structure parvalbumin interneurons. Previously, adult male mice subjected to early-life stress were found susceptible to anxiety-like behaviors, with accompanying OTX2 expression changes in ventral tegmental area or choroid plexus. Here, we investigated the consequences of reduced OTX2 levels in Otx2 heterozygote mice, as well as in Otx2
+/AA and scFvOtx2tg/0 mouse models for decreasing OTX2 transfer from choroid plexus to parvalbumin interneurons. Both male and female adult mice show anxiolysis-like phenotypes in all three models. In Otx2 heterozygote mice, we observed no changes in dopaminergic neuron numbers and morphology in ventral tegmental area, nor in their metabolic output and projections to target structures. However, we found reduced expression of parvalbumin in medial prefrontal cortex, which could be rescued in part by adult overexpression of Otx2 specifically in choroid plexus, resulting in increased anxiety-like behavior. Taken together, OTX2 synthesis by the choroid plexus followed by its secretion into the cerebrospinal fluid is an important regulator of anxiety-related phenotypes in the mouse., (© 2021. The Author(s).)- Published
- 2021
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20. Correction: Non-cell-autonomous OTX2 transcription factor regulates anxiety-related behavior in the mouse.
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Vincent C, Gilabert-Juan J, Gibel-Russo R, Alvarez-Fischer D, Krebs MO, Le Pen G, Prochiantz A, and Di Nardo AA
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- 2021
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21. Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias.
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González-Martínez J, Cwetsch AW, Martínez-Alonso D, López-Sainz LR, Almagro J, Melati A, Gómez J, Pérez-Martínez M, Megías D, Boskovic J, Gilabert-Juan J, Graña-Castro O, Pierani A, Behrens A, Ortega S, and Malumbres M
- Subjects
- Animals, Brain cytology, Brain pathology, CRISPR-Cas Systems genetics, Calmodulin-Binding Proteins genetics, Calmodulin-Binding Proteins metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Centrioles pathology, Disease Models, Animal, Embryo, Mammalian, Female, Humans, Male, Mice, Mice, Knockout, Microcephaly pathology, Microscopy, Electron, Transmission, Molecular Imaging, Mutation, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neural Stem Cells cytology, Neural Stem Cells ultrastructure, Primary Cell Culture, Time-Lapse Imaging, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Centrioles genetics, Chromosomal Instability, Microcephaly genetics, Neural Stem Cells pathology
- Abstract
Congenital microcephaly (MCPH) is a neurodevelopmental disease associated with mutations in genes encoding proteins involved in centrosomal and chromosomal dynamics during mitosis. Detailed MCPH pathogenesis at the cellular level is still elusive, given the diversity of MCPH genes and lack of comparative in vivo studies. By generating a series of CRISPR/Cas9-mediated genetic KOs, we report here that - whereas defects in spindle pole proteins (ASPM, MCPH5) result in mild MCPH during development - lack of centrosome (CDK5RAP2, MCPH3) or centriole (CEP135, MCPH8) regulators induces delayed chromosome segregation and chromosomal instability in neural progenitors (NPs). Our mouse model of MCPH8 suggests that loss of CEP135 results in centriole duplication defects, TP53 activation, and cell death of NPs. Trp53 ablation in a Cep135-deficient background prevents cell death but not MCPH, and it leads to subcortical heterotopias, a malformation seen in MCPH8 patients. These results suggest that MCPH in some MCPH patients can arise from the lack of adaptation to centriole defects in NPs and may lead to architectural defects if chromosomally unstable cells are not eliminated during brain development.
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- 2021
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22. Δ-9-Tetrahydrocannabinol treatment during adolescence and alterations in the inhibitory networks of the adult prefrontal cortex in mice subjected to perinatal NMDA receptor antagonist injection and to postweaning social isolation.
- Author
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Garcia-Mompo C, Curto Y, Carceller H, Gilabert-Juan J, Rodriguez-Flores E, Guirado R, and Nacher J
- Subjects
- Adolescent, Adult, Animals, Humans, Interneurons metabolism, Mice, Prefrontal Cortex metabolism, Social Isolation, Dronabinol pharmacology, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
The prefrontal cortex (PFC) continues its development during adolescence and alterations in its structure and function, particularly of inhibitory networks, have been detected in schizophrenic patients. Since cannabis use during adolescence is a risk factor for this disease, our main objective was to investigate whether THC administration during this period might exacerbate alterations in prefrontocortical inhibitory networks in mice subjected to a perinatal injection of MK801 and postweaning social isolation. This double-hit model (DHM) combines a neurodevelopmental manipulation and the exposure to an aversive experience during early life; previous work has shown that DHM mice have important alterations in the structure and connectivity of PFC interneurons. In the present study we found that DHM had reductions in prepulse inhibition of the startle reflex (PPI), GAD67 expression and cingulate 1 cortex volume. Interestingly, THC by itself induced increases in PPI and decreases in the dendritic complexity of somatostatin expressing interneurons. Both THC and DHM reduced the density of parvalbumin expressing cells surrounded by perineuronal nets and, when combined, they disrupted the ratio between the density of puncta expressing excitatory and inhibitory markers. Our results support previous work showing alterations in parameters involving interneurons in similar animal models and schizophrenic patients. THC treatment does not modify further these parameters, but changes some others related also to interneurons and their plasticity, in some cases in the opposite direction to those induced by the DHM, suggesting a protective effect.
- Published
- 2020
- Full Text
- View/download PDF
23. Cell Metabolic Alterations due to Mcph1 Mutation in Microcephaly.
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Journiac N, Gilabert-Juan J, Cipriani S, Benit P, Liu X, Jacquier S, Faivre V, Delahaye-Duriez A, Csaba Z, Hourcade T, Melinte E, Lebon S, Violle-Poirsier C, Oury JF, Adle-Biassette H, Wang ZQ, Mani S, Rustin P, Gressens P, and Nardelli J
- Subjects
- Animals, Cell Cycle Proteins metabolism, Cell Differentiation genetics, Cell Proliferation genetics, Cell Survival genetics, Cytoskeletal Proteins metabolism, Female, HEK293 Cells, HSP70 Heat-Shock Proteins genetics, HSP70 Heat-Shock Proteins metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Microcephaly physiopathology, Mitochondria metabolism, Mitochondrial Proteins genetics, Mitochondrial Proteins metabolism, Mutation, Nerve Tissue Proteins metabolism, Neurogenesis genetics, Neuroglia metabolism, Neurons metabolism, Voltage-Dependent Anion Channel 1 genetics, Voltage-Dependent Anion Channel 1 metabolism, Cell Cycle Proteins genetics, Cytoskeletal Proteins genetics, Microcephaly genetics, Microcephaly metabolism
- Abstract
A distinctive feature of neocortical development is the highly coordinated production of different progenitor cell subtypes, which are critical for ensuring adequate neurogenic outcome and the development of normal neocortical size. To further understand the mechanisms that underlie neocortical growth, we focused our studies on the microcephaly gene Mcph1, and we report here that Mcph1 (1) exerts its functions in rapidly dividing apical radial glial cells (aRGCs) during mouse neocortical development stages that precede indirect neurogenesis; (2) is expressed at mitochondria; and (3) controls the proper proliferation and survival of RGCs, potentially through crosstalk with cellular metabolic pathways involving the stimulation of mitochondrial activity via VDAC1/GRP75 and AKT/HK2/VDAC1 and glutaminolysis via ATF4/PCK2. We currently report the description of a MCPH-gene implication in the interplay between bioenergetic pathways and neocortical growth, thus pointing to alterations of cellular metabolic pathways, in particular glutaminolysis, as a possible cause of microcephalic pathogenesis., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Institut National de la Sante et de la Recherche Médicale. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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24. Reduced interneuronal dendritic arborization in CA1 but not in CA3 region of mice subjected to chronic mild stress.
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Gilabert-Juan J, Bueno-Fernandez C, Castillo-Gomez E, and Nacher J
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- Animals, Cell Count, Dendritic Spines enzymology, Interneurons cytology, Interneurons enzymology, Male, Mice, Neural Cell Adhesion Molecule L1 metabolism, Sialic Acids metabolism, CA1 Region, Hippocampal cytology, CA1 Region, Hippocampal enzymology, CA1 Region, Hippocampal physiopathology, CA3 Region, Hippocampal cytology, CA3 Region, Hippocampal enzymology, CA3 Region, Hippocampal physiopathology, Dendritic Spines physiology, Glutamate Decarboxylase metabolism, Interneurons physiology, Neuronal Plasticity physiology, Stress, Psychological enzymology, Stress, Psychological physiopathology
- Abstract
Introduction: Chronic stress induces dendritic atrophy and decreases spine density in excitatory hippocampal neurons, although there is also ample evidence indicating that the GABAergic system is altered in the hippocampus after this aversive experience. Chronic stress causes dendritic remodeling both in excitatory neurons and interneurons in the medial prefrontal cortex and the amygdala., Methods: In order to know whether it also has an impact on the structure and neurotransmission of hippocampal interneurons, we have analyzed the dendritic arborization, spine density, and the expression of markers of inhibitory synapses and plasticity in the hippocampus of mice submitted to 21 days of mild restrain stress. The analyses were performed in GIN mice, a strain that displays EGFP-labeled interneurons., Results: We observed a significant decrease in the dendritic arborization of interneurons in the CA1 region, which did not occur in those in CA3. We found neither changes in dendritic spine density in these regions nor alterations in the number of EGFP-positive interneurons. Nevertheless, the expression of glutamic acid decarboxylase 67 was reduced in different layers of CA1 and CA3 regions of the hippocampus. No significant changes were found in the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) or synaptophysin., Conclusions: Chronic stress reduces the interneuronal dendritic arborization in CA1 region of the hippocampus but not in CA3.
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- 2016
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25. Altered distribution of hippocampal interneurons in the murine Down Syndrome model Ts65Dn.
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Hernández-González S, Ballestín R, López-Hidalgo R, Gilabert-Juan J, Blasco-Ibáñez JM, Crespo C, Nácher J, and Varea E
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- Animals, Calcium-Binding Proteins metabolism, Down Syndrome genetics, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins metabolism, Neuropeptides metabolism, Neuropil pathology, Synapses drug effects, Synapses metabolism, Down Syndrome pathology, Hippocampus pathology, Interneurons pathology
- Abstract
Down Syndrome, with an incidence of one in 800 live births, is the most common genetic alteration producing intellectual disability. We have used the Ts65Dn model, that mimics some of the alterations observed in Down Syndrome. This genetic alteration induces an imbalance between excitation and inhibition that has been suggested as responsible for the cognitive impairment present in this syndrome. The hippocampus has a crucial role in memory processing and is an important area to analyze this imbalance. In this report we have analysed, in the hippocampus of Ts65Dn mice, the expression of synaptic markers: synaptophysin, vesicular glutamate transporter-1 and isoform 67 of the glutamic acid decarboxylase; and of different subtypes of inhibitory neurons (Calbindin D-28k, parvalbumin, calretinin, NPY, CCK, VIP and somatostatin). We have observed alterations in the inhibitory neuropil in the hippocampus of Ts65Dn mice. There was an excess of inhibitory puncta and a reduction of the excitatory ones. In agreement with this observation, we have observed an increase in the number of inhibitory neurons in CA1 and CA3, mainly interneurons expressing calbindin, calretinin, NPY and VIP, whereas parvalbumin cell numbers were not affected. These alterations in the number of interneurons, but especially the alterations in the proportion of the different types, may influence the normal function of inhibitory circuits and underlie the cognitive deficits observed in DS.
- Published
- 2015
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26. Astrocytes of the murine model for Down Syndrome Ts65Dn display reduced intracellular ionic zinc.
- Author
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Ballestín R, Blasco-Ibáñez JM, Crespo C, Nacher J, López-Hidalgo R, Gilabert-Juan J, Moltó D, and Varea E
- Subjects
- Animals, Cells, Cultured, Female, Homeostasis, Mice, Mice, Inbred C3H, Astrocytes metabolism, Disease Models, Animal, Down Syndrome metabolism, Zinc metabolism
- Abstract
Zinc is an essential trace element that is critical for a large number of structural proteins, enzymatic processes and transcription factors. In the brain, zinc ions are involved in synaptic transmission. The homeostasis of zinc is crucial for cell survival and function, and cells have developed a wide variety of systems to control zinc concentration. Alterations in free zinc concentration have been related with brain dysfunction. Down Syndrome individuals present alterations in free zinc concentration and in some of the proteins related with zinc homeostasis. We have analyzed the amount of free zinc and the zinc chelating protein metallothionein 3 in the astrocytes using primary cultures of the murine model Ts65Dn. We have observed a higher number of zinc positive spots in the cytoplasm of trisomic astrocytes but a decrease in the total concentration of total intracellular free zinc concentration (including the spots) respect to control astrocytes. Using FM1-43 staining, we found that the endocytic function remains unaltered. Therefore, a possible explanation for this lower concentration of free zinc could be the higher concentration of metallothionein 3 present in the cytoplasm of trisomic astrocytes. The blockade of metallothionein 3 expression using an specific siRNA induced an increase in the concentration of free zinc in basal conditions but failed to increase the uptake of zinc after incubation with zinc ions., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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27. Sex-specific association of the ST8SIAII gene with schizophrenia in a Spanish population.
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Gilabert-Juan J, Nacher J, Sanjuán J, and Moltó MD
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- Alleles, Female, Genetic Predisposition to Disease genetics, Genotype, Haplotypes genetics, Humans, Male, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, Schizophrenia ethnology, Sex Factors, Spain epidemiology, White People psychology, Schizophrenia genetics, Sialyltransferases genetics, White People genetics
- Abstract
We investigated the association between ST8SIAII and schizophrenia in a sample of Spanish origin. We found that the G allele (P=0.044) and the AG genotype (P=0.040) of rs3759916 were associated in females. The ACAG haplotype (rs3759914, rs3759915, rs3759916 and rs2305561) was associated in males (P=0.028)., (© 2013 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2013
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28. A "double hit" murine model for schizophrenia shows alterations in the structure and neurochemistry of the medial prefrontal cortex and the hippocampus.
- Author
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Gilabert-Juan J, Belles M, Saez AR, Carceller H, Zamarbide-Fores S, Moltó MD, and Nacher J
- Subjects
- Animals, Animals, Newborn, Body Weight drug effects, Disease Models, Animal, Dizocilpine Maleate administration & dosage, Excitatory Amino Acid Antagonists administration & dosage, Female, Gene Expression Regulation drug effects, Male, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neural Cell Adhesion Molecules genetics, Neural Cell Adhesion Molecules metabolism, Pregnancy, Proto-Oncogene Proteins c-fos metabolism, Rats, Schizophrenia etiology, Social Isolation, Gene Expression Regulation physiology, Hippocampus metabolism, Hippocampus pathology, Prefrontal Cortex metabolism, Prefrontal Cortex pathology, Schizophrenia pathology
- Abstract
Both alterations in neurodevelopment and aversive experiences during childhood and adolescence seem important risk factors for schizophrenia. Animal models reproducing these alterations mimic some of the symptoms, constituting a valid approach to study the etiopathology of this disorder. Among these models, the perinatal injection of N-methyl-d-aspartate receptor antagonists and the postweaning social isolation rearing are among the most widely used. Our aim is to combine them in a "double hit" model, which should produce a wider spectrum of alterations. Lister Hooded rats have been subjected to a single injection of MK-801 at postnatal day 7 and socially isolated from postweaning to adulthood. These animals presented increased body weight gain and volume reductions in their medial prefrontal cortex (mPFC) and hippocampus. They also showed an increased number of activated pyramidal neurons and alterations in the numbers of parvalbumin and calbindin expressing interneurons in the mPFC. The expressions of the polysialylated form of the neural cell adhesion molecule and GAD67 are decreased in the mPFC. The mRNA level of calbindin was decreased, while that of calretinin was increased in the mPFC. The mRNA level of ERbB4, a gene associated to schizophrenia, was also altered in this region. All these structural and neurochemical alterations, specially in cortical inhibitory circuits, are similar to those found in schizophrenic patients and are more numerous than in each of the single models. Consequently, the present "double hit" model may be a better tool to study the neurobiological basis of schizophrenia and to explore new therapeutic approaches., (© 2013.)
- Published
- 2013
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29. Chronic stress alters inhibitory networks in the medial prefrontal cortex of adult mice.
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Gilabert-Juan J, Castillo-Gomez E, Guirado R, Moltó MD, and Nacher J
- Subjects
- Animals, DNA Primers genetics, Dendrites physiology, Gene Expression Regulation genetics, Glutamate Decarboxylase metabolism, Immunohistochemistry, Interneurons metabolism, Male, Mice, Microscopy, Confocal, Neural Cell Adhesion Molecules metabolism, Prefrontal Cortex cytology, Reverse Transcriptase Polymerase Chain Reaction, Synaptophysin metabolism, Gene Expression Regulation physiology, Interneurons cytology, Models, Neurological, Neuronal Plasticity physiology, Prefrontal Cortex physiology, Stress, Physiological physiology, Synaptic Transmission genetics
- Abstract
Chronic stress in experimental animals induces dendritic atrophy and decreases spine density in principal neurons of the medial prefrontal cortex (mPFC). This structural plasticity may play a neuroprotective role and underlie stress-induced behavioral changes. Different evidences indicate that the prefrontocortical GABA system is also altered by stress and in major depression patients. In the amygdala, chronic stress induces dendritic remodeling both in principal neurons and in interneurons. However, it is not known whether similar structural changes occur in mPFC interneurons. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these changes, because it is known to influence the dendritic organization of adult cortical interneurons. We have analyzed the dendritic arborization and spine density of mPFC interneurons in adult mice after 21 days of restraint stress and have found dendritic hypertrophy in a subpopulation of interneurons identified mainly as Martinotti cells. This aversive experience also decreases the number of glutamate decarboxylase enzyme, 67 kDa isoform (GAD67) expressing somata, without affecting different parameters related to apoptosis, but does not alter the number of interneurons expressing PSA-NCAM. Quantitative retrotranscription-polymerase chain reaction (qRT-PCR) analysis of genes related to general and inhibitory neurotransmission and of PSA synthesizing enzymes reveals increases in the expression of NCAM, synaptophysin and GABA(A)α1. Together these results show that mPFC inhibitory networks are affected by chronic stress and suggest that structural plasticity may be an important feature of stress-related psychiatric disorders where this cortical region, specially their GABAergic system, is altered.
- Published
- 2013
- Full Text
- View/download PDF
30. Alterations in the expression of PSA-NCAM and synaptic proteins in the dorsolateral prefrontal cortex of psychiatric disorder patients.
- Author
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Gilabert-Juan J, Varea E, Guirado R, Blasco-Ibáñez JM, Crespo C, and Nácher J
- Subjects
- Adult, Aged, Amygdala metabolism, Amygdala pathology, Bipolar Disorder metabolism, Bipolar Disorder pathology, Depressive Disorder, Major metabolism, Depressive Disorder, Major pathology, Hippocampus metabolism, Hippocampus pathology, Humans, Mental Disorders pathology, Middle Aged, Neural Inhibition physiology, Neuronal Plasticity physiology, Prefrontal Cortex pathology, Schizophrenia metabolism, Schizophrenia pathology, Synapses metabolism, Glutamate Decarboxylase metabolism, Mental Disorders metabolism, Neural Cell Adhesion Molecule L1 metabolism, Prefrontal Cortex metabolism, Sialic Acids metabolism, Synaptophysin metabolism, Vesicular Glutamate Transport Protein 1 metabolism
- Abstract
Alterations in the structure and physiology of the prefrontal cortex (PFC) have been found in different psychiatric disorders and some of them involve inhibitory networks, especially in schizophrenia and major depression. Changes in the structure of these networks may be mediated by the polysialylated neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity, expressed in the PFC exclusively by interneurons. Different studies have found that PSA-NCAM expression in the hippocampus and the amygdala is altered in schizophrenia, major depression and animal models of these disorders, in parallel to changes in the expression of molecules related to inhibitory neurotransmission and synaptic plasticity. We have analyzed post-mortem sections of the dorsolateral PFC from the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients, to check whether similar alterations occur. PSA-NCAM was found in neuronal somata and neuropil puncta, many of which corresponded to interneurons. PSA-NCAM expression was only reduced significantly in schizophrenic patients, in parallel to a decrease in glutamic acid-decarboxylase-67 (GAD67) and to an increased expression of vesicular glutamate transporter 1 (VGLUT1) in the white matter. Depressed patients showed significant decreases in synaptophysin (SYN) and VGLUT1 expression. Whereas in bipolar patients, decreases in VGLUT1 expression have also been found, together with a reduction of GAD67. These results indicate that the expression of synaptic proteins is altered in the PFC of patients suffering from these disorders and that, particularly in schizophrenia, abnormal PSA-NCAM and GAD67 expression may underlie the alterations observed in inhibitory neurotransmission., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
31. Post-weaning social isolation rearing influences the expression of molecules related to inhibitory neurotransmission and structural plasticity in the amygdala of adult rats.
- Author
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Gilabert-Juan J, Moltó MD, and Nacher J
- Subjects
- Animals, Densitometry, Female, Glutamate Decarboxylase biosynthesis, Glutamate Decarboxylase genetics, Immunohistochemistry, Interneurons metabolism, Neural Cell Adhesion Molecule L1 metabolism, Neural Cell Adhesion Molecules biosynthesis, Neural Cell Adhesion Molecules genetics, Neuropil metabolism, Pregnancy, RNA, Messenger biosynthesis, RNA, Messenger genetics, Rats, Real-Time Polymerase Chain Reaction, Sialic Acids metabolism, Synaptophysin biosynthesis, Synaptophysin genetics, Amygdala metabolism, Neuronal Plasticity genetics, Neuronal Plasticity physiology, Social Isolation psychology, Synaptic Transmission genetics, Synaptic Transmission physiology
- Abstract
Several lines of evidence indicate that alterations in the structure of neural circuits and inhibitory neurotransmission underlie the physiopathogenesis of schizophrenia. Most of the studies on these parameters have been focused on cortical regions and, despite the crucial role of the amygdala in this psychiatric disorder, there is less information on this region. In order to expand this knowledge, we have studied the expression of molecules related to inhibitory neurotransmission and structural plasticity in rats subjected to post-weaning isolation rearing, an animal model that reproduces several core symptoms of schizophrenia. We have analyzed, using qRT-PCR and immunohistochemistry, the expression of synaptophysin, GAD65, GAD67, the neural cell adhesion molecule (NCAM), its polysialylated form (PSA-NCAM) and its synthesizing enzymes (St8siaII and St8SiaIV). Isolation-reared rats showed significant increases in the expression of GAD67 protein in the centromedial, medial and basolateral amygdaloid nuclei, but no significant changes in GAD65 or synaptophysin expression were found in these regions. The expression of PSA-NCAM and NCAM was significantly increased in the basolateral and medial nuclei respectively. Our results indicate that isolation-rearing influences positively inhibitory neurotransmission and neuronal structural plasticity in the amygdala, probably through PSA-NCAM. These findings are in contrast to reports describing decreased expression of molecules related to inhibitory neurotransmission in the amygdala of schizophrenic patients. Consequently, although the social isolation rearing model can reproduce some of the behavioral traits of schizophrenics it may fail to reproduce some of the neurobiological features of this disorder, particularly in the amygdala., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
32. Altered expression of neuropeptides in the primary somatosensory cortex of the Down syndrome model Ts65Dn.
- Author
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Hernández S, Gilabert-Juan J, Blasco-Ibáñez JM, Crespo C, Nácher J, and Varea E
- Subjects
- Animals, Calcium-Binding Proteins metabolism, Disease Models, Animal, Down Syndrome pathology, Hippocampus metabolism, Hippocampus pathology, Interneurons metabolism, Interneurons pathology, Male, Mice, Neurons metabolism, Somatosensory Cortex pathology, Somatostatin metabolism, Down Syndrome metabolism, Neuropeptides metabolism, Somatosensory Cortex metabolism
- Abstract
Down syndrome is the most common genetic disorder associated with mental retardation. Subjects and mice models for Down syndrome (such as Ts65Dn) show defects in the formation of neuronal networks in both the hippocampus and the cerebral cortex. The principal neurons display alterations in the morphology, density and distribution of dendritic spines in the cortex as well as in the hippocampus. Several evidences point to the possibility that the atrophy observed in principal neurons could be mediated by changes in their inhibitory inputs and, in fact, an imbalance between excitation and inhibition has been observed in Ts65Dn mice in these regions, which are crucial for learning and information processing. These animals have an increased density of interneurons in the primary somatosensory cortex, especially of those expressing calretinin and calbindin D-28k. Here, we have analysed the expression and distribution of several neuropeptides in the primary somatosensory cortex of Ts65Dn mice in order to investigate whether these subpopulations of interneurons are affected. We have observed an increase in the total density of somatostatin expressing interneurons and of those expressing VIP in layer IV in Ts65Dn mice. The typology of the somatostatin and VIP interneurons was unaltered as attested by the pattern of co-expression with other markers. Somatostatin immunoreactive neurons co-express mainly D-28k calbindin and VIP expressing interneurons maintain its pattern of co-expression with calcium binding proteins. These alterations, in case they were also present in subjects with Down syndrome, could be related to their impairment in cognitive profile and could be involved in the neurological defects observed in this disorder., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
33. Expression of PSA-NCAM and synaptic proteins in the amygdala of psychiatric disorder patients.
- Author
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Varea E, Guirado R, Gilabert-Juan J, Martí U, Castillo-Gomez E, Blasco-Ibáñez JM, Crespo C, and Nacher J
- Subjects
- Acetylcholinesterase metabolism, Adult, Aged, Amygdala pathology, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Female, Gene Expression Regulation physiology, Humans, Male, Middle Aged, Neurons metabolism, Phosphopyruvate Hydratase metabolism, Postmortem Changes, Synaptophysin metabolism, Amygdala metabolism, Glutamate Decarboxylase metabolism, Mood Disorders pathology, Neural Cell Adhesion Molecule L1 metabolism, Schizophrenia pathology, Sialic Acids metabolism, Vesicular Glutamate Transport Protein 1 metabolism
- Abstract
Neuroimaging has revealed structural abnormalities in the amygdala of different psychiatric disorders. The polysialylated neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity, which expression is altered in schizophrenia, major depression and in animal models of these disorders, may participate in these changes. However, PSA-NCAM has not been studied in the human amygdala. To know whether its expression and that of presynaptic markers, was affected in psychiatric disorders, we have analyzed post-mortem sections from the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients. PSA-NCAM was expressed in neuronal somata and neuropil puncta, many of which corresponded to interneurons. Depressed patients showed decreases in PSA-NCAM expression in the basolateral and basomedial amygdala; synaptophysin and GAD67 were also decreased, while VGLUT-1 was increased, in different nuclei. Increases in PSA-NCAM expression were found in the lateral nucleus of bipolar patients; synaptophysin and GAD67 were reduced, and VGLUT-1 increased, in their basolateral and lateral nuclei. The expression of synaptophysin and GAD67 was downregulated in the basolateral nucleus of schizophrenics. These results indicate that inhibitory and excitatory amygdaloid circuits are affected in these disorders and that abnormal PSA-NCAM expression in depressive and bipolar patients may underlie these alterations., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
34. Chronic stress induces changes in the structure of interneurons and in the expression of molecules related to neuronal structural plasticity and inhibitory neurotransmission in the amygdala of adult mice.
- Author
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Gilabert-Juan J, Castillo-Gomez E, Pérez-Rando M, Moltó MD, and Nacher J
- Subjects
- Amygdala pathology, Animals, Dendrites metabolism, Dendrites pathology, Dendritic Spines metabolism, Dendritic Spines pathology, Disease Models, Animal, Glutamate Decarboxylase genetics, Immobilization, Immunohistochemistry, Interneurons pathology, Male, Mice, Neural Cell Adhesion Molecule L1 genetics, Neuronal Plasticity, Sialic Acids genetics, Sialyltransferases genetics, Stress, Psychological pathology, Synaptic Transmission, Synaptophysin metabolism, Amygdala metabolism, Glutamate Decarboxylase metabolism, Interneurons metabolism, Neural Cell Adhesion Molecule L1 metabolism, Sialic Acids metabolism, Sialyltransferases metabolism, Stress, Psychological metabolism
- Abstract
Chronic stress in experimental animals, one of the most accepted models of chronic anxiety and depression, induces structural remodeling of principal neurons in the amygdala and increases its excitation by reducing inhibitory tone. These changes may be mediated by the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity and expressed by interneurons in the adult CNS, which is downregulated in the amygdala after chronic stress. We have analyzed the amygdala of adult mice after 21 days of restraint stress, studying with qRT-PCR the expression of genes related to general and inhibitory neurotransmission, and of PSA synthesizing enzymes. The expression of GAD67, synaptophysin and PSA-NCAM was also studied in specific amygdaloid nuclei using immunohistochemistry. We also analyzed dendritic arborization and spine density, and cell activity, monitoring c-Fos expression, in amygdaloid interneurons. At the mRNA level, the expression of GAD67 and of St8SiaII was significantly reduced. At the protein level there was an overall reduction in the expression of GAD67, synaptophysin and PSA-NCAM, but significant changes were only detected in specific amygdaloid regions. Chronic stress did not affect dendritic spine density, but reduced dendritic arborization in interneurons of the lateral and basolateral amygdala. These results indicate that chronic stress modulates inhibitory neurotransmission in the amygdala by regulating the expression of molecules involved in this process and by promoting the structural remodeling of interneurons. The addition of PSA to NCAM by St8SiaII may be involved in these changes., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
35. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is expressed in a subpopulation of mature cortical interneurons characterized by reduced structural features and connectivity.
- Author
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Gómez-Climent MÁ, Guirado R, Castillo-Gómez E, Varea E, Gutierrez-Mecinas M, Gilabert-Juan J, García-Mompó C, Vidueira S, Sanchez-Mataredona D, Hernández S, Blasco-Ibáñez JM, Crespo C, Rutishauser U, Schachner M, and Nacher J
- Subjects
- Animals, Cell Shape genetics, Cerebral Cortex pathology, Interneurons pathology, Male, Neural Cell Adhesion Molecule L1 biosynthesis, Neural Pathways metabolism, Neural Pathways pathology, Neural Pathways physiopathology, Neurogenesis genetics, Neuronal Plasticity genetics, Rats, Rats, Sprague-Dawley, Sialic Acids biosynthesis, Cell Differentiation genetics, Cerebral Cortex metabolism, Interneurons metabolism, Neural Cell Adhesion Molecule L1 genetics, Neural Inhibition genetics, Sialic Acids genetics
- Abstract
Principal neurons in the adult cerebral cortex undergo synaptic, dendritic, and spine remodeling in response to different stimuli, and several reports have demonstrated that the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) participates in these plastic processes. However, there is only limited information on the expression of this molecule on interneurons and on its role in the structural plasticity of these cells. We have found that PSA-NCAM is expressed in mature interneurons widely distributed in all the extension of the cerebral cortex and have excluded the expression of this molecule in most principal cells. Although PSA-NCAM expression is generally considered a marker of immature neurons, birth-dating analyses reveal that these interneurons do not have an adult or perinatal origin and that they are generated during embryonic development. PSA-NCAM expressing interneurons show reduced density of perisomatic and peridendritic puncta expressing different synaptic markers and receive less perisomatic synapses, when compared with interneurons lacking this molecule. Moreover, they have reduced dendritic arborization and spine density. These data indicate that PSA-NCAM expression is important for the connectivity of interneurons in the adult cerebral cortex and that its regulation may play an important role in the structural plasticity of inhibitory networks.
- Published
- 2011
- Full Text
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36. Potential involvement of serotonin receptor genes with age of onset and gender in schizophrenia: a preliminary study in a Spanish sample.
- Author
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Gilabert-Juan J, Ivorra JL, Tolosa A, Gratacòs M, Costas J, Sanjuán J, and Moltó MD
- Subjects
- Female, Humans, Male, Polymorphism, Single Nucleotide genetics, Spain ethnology, Age of Onset, Receptors, Serotonin genetics, Schizophrenia genetics, Sex Characteristics
- Published
- 2011
- Full Text
- View/download PDF
37. [The genetics of child temperament].
- Author
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Ivorra-Martínez J, Gilabert-Juan J, Moltó-Ruiz MD, and Sanjuán J
- Subjects
- Adoption, Animals, Child, Preschool, Family psychology, Humans, Monoamine Oxidase genetics, Polymorphism, Genetic, Receptors, Dopamine D4 genetics, Serotonin Plasma Membrane Transport Proteins genetics, Twins genetics, Behavior physiology, Temperament physiology
- Abstract
Introduction: In spite of the high initial expectancy in preliminary results concerning the genetics of personality, these studies have not provided satisfactory results. The failure could be related to the lack of biological validity of personality concept and the important influence of environmental factors on personality. A possible way to solve this problem is to look at the temperament of preschool children. It is expected that variability in infants' behaviour can be better defined and with less environmental influence., Development: Firstly, twin and adoption studies of child temperament in comparison with the studies of personality in adults are reviewed. Secondly, the molecular association studies carried out concerning child temperament are analyzed. The serotonin transporter gene (5-HTT), D4 receptor gene (DRD4) and mono amino oxidade-A gene (MAOA) have been considered candidates to explain variability in child temperament because these genes have been related with specific personality dimensions and mental diseases. Finally, the methodological problems and the future direction of research in this field are considered., Conclusions: Heritability shows higher values in infant temperament than in adult personality. Different gene polymorphisms on 5-HTT, DRD4 and MAOA could explain some individual variability in children's behavior, although replication studies are needed to confirm the role of these genes. Longitudinal studies in large samples that include gene and environmental interactions are one of the best ways to improve our knowledge about the genetics of child temperament.
- Published
- 2007
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