58 results on '"Olga Peñagarikano"'
Search Results
2. Current Techniques for Investigating the Brain Extracellular Space
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Federico N. Soria, Cristina Miguelez, Olga Peñagarikano, and Jan Tønnesen
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single particle tracking ,STED microscopy ,brain parenchyma ,glymphatic system ,super-resolution ,real-time iontophoresis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The brain extracellular space (ECS) is a continuous reticular compartment that lies between the cells of the brain. It is vast in extent relative to its resident cells, yet, at the same time the nano- to micrometer dimensions of its channels and reservoirs are commonly finer than the smallest cellular structures. Our conventional view of this compartment as largely static and of secondary importance for brain function is rapidly changing, and its active dynamic roles in signaling and metabolite clearance have come to the fore. It is further emerging that ECS microarchitecture is highly heterogeneous and dynamic and that ECS geometry and diffusional properties directly modulate local diffusional transport, down to the nanoscale around individual synapses. The ECS can therefore be considered an extremely complex and diverse compartment, where numerous physiological events are unfolding in parallel on spatial and temporal scales that span orders of magnitude, from milliseconds to hours, and from nanometers to centimeters. To further understand the physiological roles of the ECS and identify new ones, researchers can choose from a wide array of experimental techniques, which differ greatly in their applicability to a given sample and the type of data they produce. Here, we aim to provide a basic introduction to the available experimental techniques that have been applied to address the brain ECS, highlighting their main characteristics. We include current gold-standard techniques, as well as emerging cutting-edge modalities based on recent super-resolution microscopy. It is clear that each technique comes with unique strengths and limitations and that no single experimental method can unravel the unknown physiological roles of the brain ECS on its own. more...
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- 2020
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Catalog
3. G Protein-Coupled Receptor Heteromers as Putative Pharmacotherapeutic Targets in Autism
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Jon DelaCuesta-Barrutia, Olga Peñagarikano, and Amaia M. Erdozain
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GPCR receptor heteromers ,pharmacotherapy ,glutamate ,oxytocin ,serotonin ,dopamine ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
A major challenge in the development of pharmacotherapies for autism is the failure to identify pathophysiological mechanisms that could be targetable. The majority of developing strategies mainly aim at restoring the brain excitatory/inhibitory imbalance described in autism, by targeting glutamate or GABA receptors. Other neurotransmitter systems are critical for the fine-tuning of the brain excitation/inhibition balance. Among these, the dopaminergic, oxytocinergic, serotonergic, and cannabinoid systems have also been implicated in autism and thus represent putative therapeutic targets. One of the latest breakthroughs in pharmacology has been the discovery of G protein-coupled receptor (GPCR) oligomerization. GPCR heteromers are macromolecular complexes composed of at least two different receptors, with biochemical properties that differ from those of their individual components, leading to the activation of different cellular signaling pathways. Interestingly, heteromers of the above-mentioned neurotransmitter receptors have been described (e.g., mGlu2–5HT2A, mGlu5–D2–A2A, D2–OXT, CB1–D2, D2–5HT2A, D1–D2, D2–D3, and OXT–5HT2A). We hypothesize that differences in the GPCR interactome may underlie the etiology/pathophysiology of autism and could drive different treatment responses, as has already been suggested for other brain disorders such as schizophrenia. Targeting GPCR complexes instead of monomers represents a new order of biased agonism/antagonism that may potentially enhance the efficacy of future pharmacotherapies. Here, we present an overview of the crosstalk of the different GPCRs involved in autism and discuss current advances in pharmacological approaches targeting them. more...
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- 2020
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4. Oxytocin as Treatment for Social Cognition, Not There Yet
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Amaia M. Erdozain and Olga Peñagarikano
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oxytocin ,social cognition ,clinical trial ,autism ,schizophrenia ,depression ,Psychiatry ,RC435-571 - Abstract
In a short time, oxytocin has progressed from being a regular hormone involved in parturition and breastfeeding to be possibly the neuromodulator that has gathered the most attention. Attributed many positive roles in the modulation of different aspects of social behavior, such as bonding, empathy, cooperation, trust, and generosity, as well as roles as a natural anxiolytic and antidepressant, the expectations on oxytocin becoming a treatment for a number of disorders with associated social deficits have dramatically raised over the last years. However, despite the field has been investigating oxytocin’s role in social behavior for over twenty years, there are still many unknowns on oxytocin’s mechanisms of action and efficiency and the increasing number of clinical trials administering oxytocin to different clinical groups seem to disagree in its properties and report in most cases conflicting results. This has led to some disappointment among researchers and clinicians as oxytocin might not be the miraculous molecule that works in a “one size fits all” fashion initially considered. Conversely, this down-side of oxytocin might merely reflect the complexity of its neurotransmission system. The current reality is that, although oxytocin seems to have potential therapeutic value, there are key questions that remain unanswered as to decide the optimal target groups and treatment course. Here, we present an overview on critical points regarding the oxytocin system in health and disease that need to be better understood to establish its therapeutic properties and to decide who could benefit the most from its treatment. more...
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- 2020
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5. Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism
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Maria T. Lazaro, Jiannis Taxidis, Tristan Shuman, Iris Bachmutsky, Taruna Ikrar, Rommel Santos, G. Mark Marcello, Apoorva Mylavarapu, Swasty Chandra, Allison Foreman, Rachna Goli, Duy Tran, Nikhil Sharma, Michelle Azhdam, Hongmei Dong, Katrina Y. Choe, Olga Peñagarikano, Sotiris C. Masmanidis, Bence Rácz, Xiangmin Xu, Daniel H. Geschwind, and Peyman Golshani more...
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Biology (General) ,QH301-705.5 - Abstract
Summary: Loss-of-function mutations in CNTNAP2 cause a syndromic form of autism spectrum disorder in humans and produce social deficits, repetitive behaviors, and seizures in mice. However, the functional effects of these mutations at cellular and circuit levels remain elusive. Using laser-scanning photostimulation, whole-cell recordings, and electron microscopy, we found a dramatic decrease in excitatory and inhibitory synaptic inputs onto L2/3 pyramidal neurons of the medial prefrontal cortex (mPFC) of Cntnap2 knockout (KO) mice, concurrent with reduced spines and synapses, despite normal dendritic complexity and intrinsic excitability. Moreover, recording of mPFC local field potentials (LFPs) and unit spiking in vivo revealed increased activity in inhibitory neurons, reduced phase-locking to delta and theta oscillations, and delayed phase preference during locomotion. Excitatory neurons showed similar phase modulation changes at delta frequencies. Finally, pairwise correlations increased during immobility in KO mice. Thus, reduced synaptic inputs can yield perturbed temporal coordination of neuronal firing in cortical ensembles. : Lazaro et al. demonstrate a decrease in synaptic inputs onto mPFC L2/3 pyramidal neurons of Cntnap2 KO mice, concurrent with reduced spines and synapses. These lead to perturbed network activity, with mPFC cells exhibiting reduced phase locking and altered preferred phases to slow LFP oscillations, which may underlie autism-related phenotypes. Keywords: oscillation, delta, theta, phase-locking, inhibition, brain state, connectivity, functional, biomarker, EEG more...
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- 2019
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6. Cerebellar associative sensory learning defects in five mouse autism models
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Alexander D Kloth, Aleksandra Badura, Amy Li, Adriana Cherskov, Sara G Connolly, Andrea Giovannucci, M Ali Bangash, Giorgio Grasselli, Olga Peñagarikano, Claire Piochon, Peter T Tsai, Daniel H Geschwind, Christian Hansel, Mustafa Sahin, Toru Takumi, Paul F Worley, and Samuel S-H Wang more...
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autism spectrum disorder ,associative learning ,cerebellum ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Sensory integration difficulties have been reported in autism, but their underlying brain-circuit mechanisms are underexplored. Using five autism-related mouse models, Shank3+/ΔC, Mecp2R308/Y, Cntnap2−/−, L7-Tsc1 (L7/Pcp2Cre::Tsc1flox/+), and patDp(15q11-13)/+, we report specific perturbations in delay eyeblink conditioning, a form of associative sensory learning requiring cerebellar plasticity. By distinguishing perturbations in the probability and characteristics of learned responses, we found that probability was reduced in Cntnap2−/−, patDp(15q11-13)/+, and L7/Pcp2Cre::Tsc1flox/+, which are associated with Purkinje-cell/deep-nuclear gene expression, along with Shank3+/ΔC. Amplitudes were smaller in L7/Pcp2Cre::Tsc1flox/+ as well as Shank3+/ΔC and Mecp2R308/Y, which are associated with granule cell pathway expression. Shank3+/ΔC and Mecp2R308/Y also showed aberrant response timing and reduced Purkinje-cell dendritic spine density. Overall, our observations are potentially accounted for by defects in instructed learning in the olivocerebellar loop and response representation in the granule cell pathway. Our findings indicate that defects in associative temporal binding of sensory events are widespread in autism mouse models. more...
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- 2015
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7. Angelman Syndrome causing UBE3A ligase displays predominantly synaptic ubiquitination activity in the mouse brain
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Ugo Mayor, Unai Alduntzin, Benoit Lectez, Natalia Presa, Nerea Osinalde, Marta Fernandez, Nagore Elu, Juanma Ramirez, Cristina Garcia-Barcena, Kerman Aloria, Andreas Frick, and Olga Peñagarikano
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Angelman Syndrome (AS) is a neurodevelopmental disorder with complex symptomatology caused by the loss of maternal allele expression of one single gene in the brain, the ubiquitin E3 ligase UBE3A. The underlying genetic basis of AS, and the phenotypes observed in both humans and in animal models of AS, have previously been extensively described. However, the molecular mechanisms regulated by UBE3A ubiquitination in the brain remain highly elusive. Previous studies have reported a number of proteins whose abundance or activity are altered in AS models, implicating various signalling pathways in the physiopathology of AS. However, the identified pathways could well be altered further downstream of UBE3A ubiquitination events. We provide the first proteomic report of UBE3A-mediated ubiquitination events in a mammalian brain. For this we have combined the bioUb mouse model with a new mouse strain moderately increasing UBE3A levels. Several proteins known to be involved in the trafficking and maintenance of neurotransmitter receptors as well as proteins relaying the signals of these synaptic receptors are shown here to be ubiquitinated by UBE3A. The identified proteins have roles in higher mental function, long term potentiation, seizures and neurodevelopmental disorders, being involved in the BDNF, RAS/ERK and TSC/mTOR signalling pathways. A reduced ubiquitination of these proteins is expected when UBE3A levels are lower, so their identification could be key to opening novel therapeutic strategies for treating Angelman Syndrome. Further work will be required to characterize how UBE3A timely orchestrates each of these multiple regulatory events in different neuronal subtypes within the human brain. more...
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- 2023
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8. Neurobiological Mechanisms of Autism Spectrum Disorder and Epilepsy, Insights from Animal Models
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Olga Peñagarikano, Teresa Sierra-Arregui, Javier Llorente, Jan Tønnesen, and Paula Gimenez Minguez
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0301 basic medicine ,Epilepsy ,Autism Spectrum Disorder ,business.industry ,Mechanism (biology) ,General Neuroscience ,Comorbidity ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Animal model ,Neurobiology ,Neurodevelopmental Disorders ,Autism spectrum disorder ,mental disorders ,medicine ,Animals ,Autism ,business ,Neuroscience ,030217 neurology & neurosurgery ,Exome sequencing - Abstract
Autism Spectrum Disorder (ASD) and epilepsy are two neurodevelopmental disorders that have a high comorbidity rate, suggesting that a common neurodevelopmental mechanism exists. However, to date there is no conclusive way to predict whether a child will develop either syndrome or both and to what degree associated phenotypes will be affected. Failure to consistently identify predictive patterns of ASD and/or epilepsy diagnosis stems from the fact that they are etiologically heterogeneous conditions and research into their neuropathological mechanisms becomes challenging. Whole genome/exome sequencing has advanced our understanding of the genetic causes of ASD and epilepsy to an extent that currently about half of all ASD as well as epilepsy cases are known to have a genetic basis. In fact, a picture is emerging of both conditions as a collection of distinct genetically defined disorders, although the role of environmental factors has also been established. A plethora of animal models, most of them based on identified human genetic mutations and a few on known environmental causes, have been developed. Animal models provide a major experimental avenue for studying the underlying cellular and molecular mechanisms of human disorders. They also provide invaluable preclinical tools that can be used to test therapeutic approaches. In this review, we first summarize the methods for validating mouse models of ASD and epilepsy. Second, we present the current models validated for the comorbidity and finally, we recapitulate the common pathomechanisms identified in these models with special emphasis on synaptic plasticity. more...
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- 2020
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9. Oxitozina erabilgarria izan al daiteke autismoan gertatzen den urritasun sozialerako?
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Amaia Maite Erdozain Fernández, Celia Ruiz de Mendoza Ruiz de Arechavaleta, and Olga Peñagarikano Ahedo
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education.field_of_study ,business.industry ,Population ,Context (language use) ,medicine.disease ,Neurodevelopmental disorder ,Oxytocin ,Autism spectrum disorder ,Social cognition ,Intervention (counseling) ,medicine ,Autism ,business ,education ,medicine.drug ,Clinical psychology - Abstract
Autism spectrum disorder is a behaviourally defined neurodevelopmental disorder. It is characterized by two core symptoms: social impairment, and repetitive, restrictive behaviours. Due to its heterogeneous clinical manifestation, complex aetiology and pathophysiology, developing targeted pharmacotherapy is currently a big challenge. Behavioural therapy is the conventional intervention for this disorder; still, most of individuals with autism receive pharmacological treatment to treat associated symptoms, but there is currently no drug available to treat the core symptomatology. Therefore, biomedical research is making an important effort to develop and test new drugs, one of which is oxytocin. Oxytocin is a peptide that acts as a neuromodulator in the central nervous system. Impairments in the oxytocin system during development can influence social behaviour, by modifying synaptic activity and plasticity. In this context, the potential therapeutic use of oxytocin is being studied for social impairment in autism. Several animal models based on monogenic forms of autism show alterations in the oxytocin system, and oxytocin administration improves their social impairments. On the other hand, a significant number of clinical trials with oxytocin in humans are underway. However, unlike research with animal models, there is discrepancy in the results, with some clinical trials showing an improvement in social cognition, whereas others found no effect. This is not unexpected due to the larger heterogeneity in the human population. Consequently, more studies are required to validate the therapeutic usefulness of oxytocin for social impairment in autism and to define which individuals could benefit the most.; Autismoaren espektroaren nahastea jokabidean definitutako garapen neurologikoaren desoreka da. Bere bereizgarri dira bi sintoma nagusi: batetik, urritasun soziala; bestetik, mugimendu errepikakorrak eta murriztaileak. Autismoaren klinikaren heterogeneotasunagatik, eta etiologia eta fisiopatologia konplexuagatik, farmakoterapia zuzendu bat garatzea da gaur egungo erronka garrantzitsua, eta portaeraren terapia da erabiltzen den ohiko interbentzioa. Hala ere, autismo kasuen %75ak tratamendu farmakologikoa jasotzen du asoziaturiko sintometarako, baina momentuz ez dago sintoma nagusietarako eraginkorrak diren farmakorik. Beraz, farmako berriak garatzeko ahalegin handia egiten ari da ikerketa biomedikoa, eta hauen artean oxitozina daukagu. Oxitozina nerbio sistema zentralean neuromodulatzaile bezala jokatzen duen peptido bat da. Ikusi da garapen goiztiarrean mutazio genetikoengatik emandako oxitozina-sistemaren porrotak jokaera sozialean eragin dezakela, aktibitate eta plastikotasun sinpatikoan eraginez. Testuinguru honetan, oxitozinak autismoaren tratamenduan izan dezakeen erabilgarritasuna eta arrakasta aztertzen ari dira. Batetik, autismoaren forma monogenikoetan oinarritutako zenbait animalia-ereduk oxitozina sisteman nolabaiteko alterazioak erakusten dute, eta hauetan oxitozinaren administrazioak urritasun sozialaren hobekuntza eragiten duela. Bestetik, gizakietan ere hainbat saio kliniko burutzen ari dira oxitozinaren erabilgarritasun terapeutikoa aztertzeko. Baina kasu honetan, animalia-ereduetan ikusi denarekin parekatuz, lortutako emaitzak ezberdinak dira elkarren artean, ikerketa batzuetan kognizio sozialean hobekuntzak ikusi direlarik, baina ez beste batzuetan. Hau ez da oso harritzekoa, gizakien artean dagoen heterogeneotasunagatik. Ondorioz, ikerketa gehiagoren beharra da oxitozinak autismoan izan dezakeen erabilgarritasuna modu sendoago batean balioztatzeko eta baita ere, zehazteko zein banakoentzat izango litzatekeen onuragarrien. more...
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- 2020
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10. UBE3A-Induced Ubiquitination Changes in the Brain Reveal the Molecular Complexity of Angelman Syndrome
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Benoit Lectez, Unai Alduntzin, Nerea Osinalde, Marta Fernandez, Nagore Elu, Juanma Ramirez, Cristina Garcia-Barcena, Natalia Presa, Kerman Aloria, Andreas Frick, Olga Peñagarikano, and Ugo Mayor
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
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11. Altered Cerebellar Response to Somatosensory Stimuli in the Cntnap2 Mouse Model of Autism
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Javier Márquez-Ruiz, Marta Fernández, Javier Llorente, Teresa Sierra-Arregui, Olga Peñagarikano, Carlos A. Sánchez-León, Shira Knafo, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission, Universidad del País Vasco, Israel Science Foundation, and Ministerio de Economía y Competitividad (España) more...
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CNTNAP2 ,Cerebellum ,Sensory processing ,cerebellum ,medicine.medical_treatment ,autism ,Sensory system ,Stimulation ,Nerve Tissue Proteins ,Biology ,Somatosensory system ,Mice ,Purkinje Cells ,sensory stimuli ,cntnap2 ,medicine ,Animals ,complex spike ,Autistic Disorder ,Mice, Knockout ,Purkinje ,Cerebellar ataxia ,General Neuroscience ,Membrane Proteins ,General Medicine ,medicine.disease ,medicine.anatomical_structure ,Vibrissae ,Autism ,Disorders of the Nervous System ,medicine.symptom ,Neuroscience ,Research Article: New Research - Abstract
Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied sensory processing in the cerebellum in a mouse model of autism, knock-out (KO) for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells (PCs) and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the Cntnap2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region on electrical stimulation of the whisker pad in alert mice and found striking differences between wild-type and Cntnap2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of PCs. These changes were accompanied by altered intrinsic properties and morphologic features of these neurons. Together, these results indicate that the Cntnap2 mouse model could provide novel insight into the pathophysiological mechanisms of autism core sensory deficits., This work was supported by the Spanish Ministry of Science (MCIU/AEl/FEDER) Grant RTI2018-101427-B-I00 (to O.P.), the ERANET-NEURON Grant nEUrotalk (to O.P.), the University of the Basque Country (UPV/EHU) Grant GIU18/094 (to O.P.), the Israel Science Foundation Grant 536/19 (to S.K.), the Spanish Ministry of Science Grant SAF2016-78071-R (to S.K.), and the Spanish Ministry of Economy (MINECO-FEDER) Grant BFU2017-89615-P (to J.M.-R.). M.F. holds the MINECO Predoctoral Fellowship BES-2016–078420, and T.S.-A. is a Basque Government predoctoral fellow (PRE-2020–2-0109). more...
- Published
- 2021
12. Altered cerebellar response to somatosensory stimuli in the Cntnap2 mouse model of autism
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Marta Fernández, Carlos A. Sánchez-León, Olga Peñagarikano, Shira Knafo, Teresa Sierra-Arregui, Javier Llorente, and Javier Márquez-Ruiz
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CNTNAP2 ,Cerebellum ,Cerebellar ataxia ,Sensory processing ,medicine.medical_treatment ,Sensory system ,Stimulation ,Biology ,medicine.disease ,Somatosensory system ,medicine.anatomical_structure ,medicine ,Autism ,medicine.symptom ,Neuroscience - Abstract
Atypical sensory processing is currently included within the diagnostic criteria of autism. The cerebellum is known to integrate sensory inputs of different modalities through its connectivity to the cerebral cortex. Interestingly, cerebellar malformations are among the most replicated features found in postmortem brain of individuals with autism. We studied cerebellar integration of sensory information in a mouse model of autism, knockout for the Cntnap2 gene. Cntnap2 is widely expressed in Purkinje cells and has been recently reported to regulate their morphology. Further, individuals with CNTNAP2 mutations display cerebellar malformations and CNTNAP2 antibodies are associated with a mild form of cerebellar ataxia. Previous studies in the Cntnap2 mouse model show an altered cerebellar sensory learning. However, a physiological analysis of cerebellar function has not been performed yet. We studied sensory evoked potentials in cerebellar Crus I/II region upon electrical stimulation of the whisker pad in alert mice and found striking differences between WT and Cntnap2 KO mice. In addition, single-cell recordings identified alterations in both sensory-evoked and spontaneous firing patterns of Purkinje cells. These changes were accompanied by altered intrinsic properties and morphological features of these neurons. Together, these results indicate that the Cntnap2 mouse model could provide novel insight into the pathophysiological mechanisms of ASD core sensory deficits. more...
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- 2021
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13. Oxytocin normalizes altered circuit connectivity for social rescue of the Cntnap2 knockout mouse
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Katrina Y. Choe, Richard A.I. Bethlehem, Martin Safrin, Hongmei Dong, Elena Salman, Ying Li, Valery Grinevich, Peyman Golshani, Laura A. DeNardo, Olga Peñagarikano, Neil G. Harris, and Daniel H. Geschwind more...
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nucleus accumbens ,1.2 Psychological and socioeconomic processes ,Autism Spectrum Disorder ,Knockout ,mouse model ,Intellectual and Developmental Disabilities (IDD) ,Autism ,1.1 Normal biological development and functioning ,Nerve Tissue Proteins ,Oxytocin ,Basic Behavioral and Social Science ,Article ,social behavior ,Mice ,Underpinning research ,Receptors ,Behavioral and Social Science ,2.1 Biological and endogenous factors ,Psychology ,Animals ,Aetiology ,Social Behavior ,Mice, Knockout ,Neurology & Neurosurgery ,brain network ,General Neuroscience ,fMRI ,functional connectivity ,Neurosciences ,Brain ,Membrane Proteins ,Brain Disorders ,Mental Health ,Receptors, Oxytocin ,Neurological ,Cognitive Sciences ,paraventricular nucleus ,iDISCO - Abstract
The neural basis of abnormal social behavior in autism spectrum disorders (ASD) remains incompletely understood. Here we used two complementary, but independent brain-wide mapping approaches, mouse resting-state fMRI and c-Fos-iDISCO+ imaging, to construct brain-wide activity and connectivity maps of the Cntnap2 knockout (KO) mouse model of ASD. At the macroscale level, we detected reduced functional coupling across social brain regions, despite general patterns of hyperconnectivity across major brain structures. Oxytocin administration, which rescues social deficits in KO mice, strongly stimulated many brain areas and normalized connectivity patterns. Notably, chemogenetically-triggered release of endogenous oxytocin strongly stimulated the nucleus accumbens (NAc), a forebrain nucleus implicated in social reward. Furthermore, NAc-targeted approaches to activate local oxytocin receptors sufficiently rescued their social deficits. Our findings establish circuit- and systems-level mechanisms of social deficits in Cntnap2 KO mice, and reveal the NAc as a region that can be modulated by oxytocin to promote social interactions. more...
- Published
- 2020
14. What we can learn from a genetic rodent model about autism
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Susanne Schmid, Andreas Frick, Olga Peñagarikano, Marta Fernández, Dorit Möhrle, and Brian L. Allman
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Social Cognition ,CNTNAP2 ,Candidate gene ,Autism Spectrum Disorder ,Cognitive Neuroscience ,Cntnap2 ,behavioral disciplines and activities ,03 medical and health sciences ,Behavioral Neuroscience ,Cell and Developmental Biology ,Mice ,0302 clinical medicine ,Animal model ,Genetic ,Genetic model ,mental disorders ,medicine ,Mechanisms ,Animals ,0501 psychology and cognitive sciences ,050102 behavioral science & comparative psychology ,Early childhood ,Autism spectrum disorder ,Fragile-X ,Social Behavior ,Behavior, Animal ,Models, Genetic ,05 social sciences ,Rodent model ,Behavioural testing ,medicine.disease ,Rats ,Disease Models, Animal ,Neuropsychology and Physiological Psychology ,Cntnap 2 ,Autism ,Perception ,Anatomy ,Stereotyped Behavior ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Autism spectrum disorders (ASD) are complex neurodevelopmental disorders that are caused by genetic and/or environmental impacts, often probably by the interaction of both. They are characterised by deficits in social communication and interaction and by restricted and repetitive behaviours and interests from early childhood on, causing significant impairment. While it is clear that no animal model captures the full complexity of ASD in humans, genetic models are extremely useful for studying specific symptoms associated with ASD and the underlying cellular and molecular mechanisms. In this review we summarize the behavioral paradigms used in rodents to model ASD symptoms as they are listed in the DSM-5. We then review existing genetic rodent models with disruptions in ASD candidate genes, and we map their phenotypes onto these behavioural paradigms. The goal of this review is to give a comprehensive overview on how ASD symptoms can be studied in animal models and to give guidance for which animal models are appropriate to study specific symptom clusters. more...
- Published
- 2020
15. Neural Circuits for Social Cognition: Implications for Autism
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Irene Mollinedo-Gajate, Marta Fernández, and Olga Peñagarikano
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0301 basic medicine ,Behavioral neuroscience ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Social neuroscience ,Social cognition ,Motor cognition ,Neural Pathways ,medicine ,Animals ,Humans ,Autistic Disorder ,Social Behavior ,medicine.diagnostic_test ,General Neuroscience ,Brain ,Social cue ,medicine.disease ,030104 developmental biology ,Autism ,Psychology ,Functional magnetic resonance imaging ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Social neuroscience, the study of the neurobiological basis of social behavior, has become a major area of current research in behavioral neuroscience and psychiatry, since many psychiatric disorders are characterized by social deficits. Social behavior refers to the behavioral response with regard to socially relevant information, and requires the perception and integration of social cues through a complex cognition process (i.e. social cognition) that involves attention, memory, motivation and emotion. Neurobiological and molecular mechanisms underlying social behavior are highly conserved across species, and inter- and intra-specific variability observed in social behavior can be explained to large extent by differential activity of this conserved neural network. Human functional magnetic resonance imaging (fMRI) studies have greatly informed about the brain structures and their connectivity networks that are important for social cognition. Animal research has been crucial for identifying specific circuits and molecular mechanisms that modulate this structural network. From a molecular neurobiology perspective, activity in these brain structures is coordinated by neuronal circuits modulated by several neurotransmitters and neuromodulators. Thus, quantitative variation in the levels, release and/or receptor density of these molecules could affect the observed behavioral response. The present review presents an overall framework of the components of the social brain circuitry and its modulation. By integrating multiple research approaches, from human fMRI studies to animal models we can start shedding light into how dysfunction in these circuits could lead to disorders of social-functioning such as Autism. more...
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- 2018
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16. Oxytocin in animal models of autism spectrum disorder
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Olga Peñagarikano
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0301 basic medicine ,Neuropeptide ,medicine.disease ,Oxytocin receptor ,Social relation ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,Developmental Neuroscience ,Oxytocin ,Autism spectrum disorder ,medicine ,Autism ,Spectrum disorder ,Psychology ,Neuroscience ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Social behavior ,medicine.drug - Abstract
Autism spectrum disorder is a behavioral disorder characterized by impairments in social interaction and communication together with the presence of stereotyped behaviors and restricted interests. Although highly genetic, its etiology is complex which correlates with the extensive heterogeneity found in its clinical manifestation, adding to the challenge of understanding its pathophysiology and develop targeted pharmacotherapies. The neuropeptide oxytocin is part of a highly conserved system involved in the regulation of social behavior, and both animal and human research have shown that variation in the oxytocin system accounts for interindividual differences in the expression of social behaviors in mammals. In autism, recent studies in human patients and animal models are starting to reveal that alterations in the oxytocin system are more common than previously anticipated. Genetic variation in the key players involved in the system (i.e., oxytocin receptor, oxytocin, and CD38) has been found associated with autism in humans, and animal models of the disorder converge in an altered oxytocin system and/or dysfunction in oxytocin related biological processes. Furthermore, oxytocin administration exerts a behavioral and neurobiological response, and thus, the oxytocin system has become a promising potential therapeutical target for autism. Animal models represent a valuable tool to aid in the research into the potential therapeutic use of oxytocin. In this review, I aim to discuss the main findings related to oxytocin research in autism with a focus on findings in animal models. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 202-213, 2017. more...
- Published
- 2017
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17. The Cerebellum and Autism: More than Motor Control
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Teresa Sierra-Arregui, Olga Peñagarikano, and Marta Fernández
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Cerebellum ,medicine.anatomical_structure ,InformationSystems_INFORMATIONSTORAGEANDRETRIEVAL ,medicine ,Autism ,Motor control ,medicine.disease ,Psychology ,Neuroscience ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) - Published
- 2019
18. Reduced Prefrontal Synaptic Connectivity and Disturbed Oscillatory Population Dynamics in the CNTNAP2 Model of Autism
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Olga Peñagarikano, Apoorva Mylavarapu, Bence Rácz, Rachna Goli, Jiannis Taxidis, Xiangmin Xu, Maria T. Lazaro, Allison Foreman, Swasty Chandra, Daniel H. Geschwind, Katrina Y. Choe, Sotiris C. Masmanidis, Nikhil Sharma, Duy Tran, Peyman Golshani, Michelle Azhdam, Rommel A. Santos, Iris Bachmutsky, Tristan Shuman, Taruna Ikrar, Hongmei Dong, and G. Mark Marcello more...
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0301 basic medicine ,Male ,CNTNAP2 ,Autism ,Medical Physiology ,Local field potential ,Electroencephalography ,Inbred C57BL ,Photostimulation ,delta ,Mice ,0302 clinical medicine ,2.1 Biological and endogenous factors ,EEG ,Aetiology ,Prefrontal cortex ,lcsh:QH301-705.5 ,Mice, Knockout ,education.field_of_study ,medicine.diagnostic_test ,Pyramidal Cells ,oscillation ,brain state ,inhibition ,Mental Health ,theta ,connectivity ,Neurological ,Excitatory postsynaptic potential ,biomarker ,Female ,Knockout ,Intellectual and Developmental Disabilities (IDD) ,1.1 Normal biological development and functioning ,Population ,Prefrontal Cortex ,Nerve Tissue Proteins ,Biology ,Inhibitory postsynaptic potential ,Basic Behavioral and Social Science ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Underpinning research ,Behavioral and Social Science ,medicine ,Genetics ,Animals ,Autistic Disorder ,education ,Intellectual and Developmental Disabilities ,Animal ,Neurosciences ,Excitatory Postsynaptic Potentials ,Membrane Proteins ,Dendrites ,Brain Disorders ,Mice, Inbred C57BL ,functional ,Disease Models, Animal ,030104 developmental biology ,lcsh:Biology (General) ,Disease Models ,Synapses ,Biochemistry and Cell Biology ,phase-locking ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Summary: Loss-of-function mutations in CNTNAP2 cause a syndromic form of autism spectrum disorder in humans and produce social deficits, repetitive behaviors, and seizures in mice. However, the functional effects of these mutations at cellular and circuit levels remain elusive. Using laser-scanning photostimulation, whole-cell recordings, and electron microscopy, we found a dramatic decrease in excitatory and inhibitory synaptic inputs onto L2/3 pyramidal neurons of the medial prefrontal cortex (mPFC) of Cntnap2 knockout (KO) mice, concurrent with reduced spines and synapses, despite normal dendritic complexity and intrinsic excitability. Moreover, recording of mPFC local field potentials (LFPs) and unit spiking in vivo revealed increased activity in inhibitory neurons, reduced phase-locking to delta and theta oscillations, and delayed phase preference during locomotion. Excitatory neurons showed similar phase modulation changes at delta frequencies. Finally, pairwise correlations increased during immobility in KO mice. Thus, reduced synaptic inputs can yield perturbed temporal coordination of neuronal firing in cortical ensembles. : Lazaro et al. demonstrate a decrease in synaptic inputs onto mPFC L2/3 pyramidal neurons of Cntnap2 KO mice, concurrent with reduced spines and synapses. These lead to perturbed network activity, with mPFC cells exhibiting reduced phase locking and altered preferred phases to slow LFP oscillations, which may underlie autism-related phenotypes. Keywords: oscillation, delta, theta, phase-locking, inhibition, brain state, connectivity, functional, biomarker, EEG more...
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- 2019
19. Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing
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Vivek Swarup, Neelroop N. Parikshak, José J. Lucas, Ivó H. Hernández, Manuel Irimia, Eulàlia Belloc, Juan Ignacio Díaz-Hernández, Jose Luis Nieto-Gonzalez, Raúl Méndez, Sara Picó, María Santos-Galindo, Daniel H. Geschwind, Pilar Navarro, Alberto Parras, Ainara Elorza, Annie Rodolosse, Rafael Fernández-Chacón, Olga Peñagarikano, Héctor Anta, UAM. Departamento de Biología, Instituto de Salud Carlos III, European Commission, Ministerio de Economía y Competitividad (España), National Institute of Mental Health (Czech Republic), Junta de Andalucía, Generalitat de Catalunya, European Research Council, Fundación Botín, Fundación BBVA, Fundación Ramón Areces, Ministerio de Ciencia e Innovación (España), National Institutes of Health (US), University of California, Larry L. Hillblom Foundation, Simons Foundation, and University of Maryland more...
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0301 basic medicine ,Male ,Polyadenylation ,genetic structures ,Autism Spectrum Disorder ,General Science & Technology ,Cytoplasmic polyadenylation element ,Transgene ,Autism ,RNA Splicing ,Mice, Transgenic ,Biology ,behavioral disciplines and activities ,Article ,Transcriptome ,03 medical and health sciences ,Mice ,MRNA polyadenylation ,mental disorders ,MD Multidisciplinary ,Animals ,Humans ,Genetic Predisposition to Disease ,RNA, Messenger ,Gene ,Genetics ,Neurons ,Multidisciplinary ,Brain ,RNA-Binding Proteins ,cytoplasmic polyadenylation ,Exons ,Biología y Biomedicina / Biología ,Phenotype ,030104 developmental biology ,RNA splicing ,Female ,Protein Binding - Abstract
Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1–4 (CPEB1–4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes., This work was supported by grants: ISCIII-CiberNed-PI2013/09 & -PI2015-2/06 (J.J.L., R.F.-C.), FEDER-PI14/00125 & -PI17/00199 (P.N.), MINECO-SAF2012-34177 & -SAF2015-65371-R (J.J.L.), FEDER-BFU2014-54122-P (R.M.), -BFU2014-55076-P (M.I.), -BFU2016-76050-P (R.F.-C.), -SEV-2012-0208 to CRG by European Union FEDER (M.I.); NIMH 5R37 MH060233, 5R01 MH09714 and 5R01 MH100027 (D.H.G.); Junta de Andalucía-P12-CTS-2232 & -CTS-600 (R.F.-C.); Generalitat de Catalunya-2014/SGR/143 (P.N.); ERC-StG-LS2-637591 (M.I.); and from Fundación Botín-Banco Santander/Santander Universities Global Division, Fundación BBVA, and Fundación Ramón Areces. A.P. was recipient of a MICINN FPI-fellowship; N.N.P. was supported by the NRSA F30 MH099886, UCLA Medical Scientist Training Program and V.S. by a Larry Hillblom Postdoctoral Fellowship. We thank the computing facilities of Extremadura Research Centre for Advanced Technologies (CETA-CIEMAT/Government of Spain), which is funded by ERDF. Tissue, biological specimens or data used in this research were obtained from the Autism BrainNet (formerly the Autism Tissue Program), which is sponsored by the Simons Foundation, and the University of Maryland Brain and Tissue Bank (a component of the NIH NeuroBioBank). more...
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- 2018
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20. Reduced prefrontal synaptic connectivity and disturbed oscillatory population dynamics in the CNTNAP2 model of autism
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Apoorva Mylavarapu, Taruna Ikrar, Hongmei Dong, Daniel H. Geschwind, Iris Bachmutsky, G. Mark Marcello, Michelle Azhdam, Olga Peñagarikano, Bence Rácz, Peyman Golshani, Duy Tran, Sotiris C. Masmanidis, Rachna Goli, Jiannis Taxidis, Allison Foreman, Tristan Shuman, Nikhil Sharma, Xiangmin Xu, Rommel A. Santos, Maria T. Lazaro, and Swasty Chandra more...
- Subjects
0303 health sciences ,education.field_of_study ,CNTNAP2 ,Population ,Local field potential ,Biology ,Inhibitory postsynaptic potential ,Photostimulation ,Synapse ,03 medical and health sciences ,0302 clinical medicine ,Excitatory postsynaptic potential ,education ,Prefrontal cortex ,Neuroscience ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Loss of function mutations in CNTNAP2 cause a syndromic form of autism spectrum disorder (ASD) in humans and produce social deficits, repetitive behaviors, and seizures in mice. Yet, the functional effects of these mutations at the cellular and circuit level remain elusive. Using laser scanning photostimulation, whole-cell recordings, and electron microscopy, we found a dramatic decrease in functional excitatory and inhibitory synaptic inputs in L2/3 medial prefrontal cortex (mPFC) of Cntnap2 knock-out (KO) mice. In accordance with decreased synaptic input, KO mice displayed reduced spine and synapse densities, despite normal intrinsic excitability and dendritic complexity. To determine how this decrease in synaptic inputs alters coordination of neuronal firing patterns in vivo, we recorded mPFC local field potentials (LFP) and unit spiking in head-fixed mice during locomotion and rest. In KO mice, LFP power was not significantly altered at all tested frequencies, but inhibitory neurons showed delayed phase-firing and reduced phase-locking to delta and theta oscillations during locomotion. Excitatory neurons showed similar changes but only to delta oscillations. These findings suggest that profound ASD-related alterations in synaptic inputs can yield perturbed temporal coordination of cortical ensembles. more...
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- 2018
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21. New Therapeutic Options for Autism Spectrum Disorder: Experimental Evidences
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Olga Peñagarikano
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Pharmacological research ,Autism ,Review Article: Autism Spectrum Disorders ,medicine.disease ,ASD ,Social relation ,Human genetics ,Pharmacotherapy ,Repetitive behavior ,Treatment ,Cellular and Molecular Neuroscience ,Autism spectrum disorder ,mental disorders ,medicine ,Neurology (clinical) ,Social behavior ,Psychology ,Clinical psychology - Abstract
Autism spectrum disorder (ASD) is characterized by impairment in two behavioral domains: social interaction/communication together with the presence of stereotyped behaviors and restricted interests. The heterogeneity in the phenotype among patients and the complex etiology of the disorder have long impeded the advancement of the development of successful pharmacotherapies. However, in the recent years, the integration of findings of multiple levels of research, from human genetics to mouse models, have made considerable progress towards the understanding of ASD pathophysiology, allowing the development of more effective targeted drug therapies. The present review discusses the current state of pharmacological research in ASD based on the emerging common pathophysiology signature. more...
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- 2015
22. Endocannabinoid signaling mediates oxytocin-driven social reward
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Daniele Piomelli, Conor D. Cox, Christine M. Gall, Daniel H. Geschwind, Olga Peñagarikano, Don Wei, DaYeon Lee, and Carley A. Karsten
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Male ,Cannabinoid receptor ,Autism Spectrum Disorder ,Polyunsaturated Alkamides ,Neuropeptide ,Arachidonic Acids ,Nucleus accumbens ,Oxytocin ,Nucleus Accumbens ,Piperazines ,Benzodiazepines ,Mice ,chemistry.chemical_compound ,Cocaine ,Piperidines ,Reward ,medicine ,Animals ,Receptors, Cannabinoid ,Social Behavior ,Clozapine ,Analysis of Variance ,Camphanes ,Multidisciplinary ,Anandamide ,Biological Sciences ,Immunohistochemistry ,Lipids ,Endocannabinoid system ,Oxytocin receptor ,Mice, Inbred C57BL ,Infusions, Intraventricular ,chemistry ,Hypothalamus ,Benzamides ,Pyrazoles ,Carbamates ,Psychology ,Neuroscience ,psychological phenomena and processes ,hormones, hormone substitutes, and hormone antagonists ,Endocannabinoids ,Signal Transduction ,medicine.drug - Abstract
Marijuana exerts profound effects on human social behavior, but the neural substrates underlying such effects are unknown. Here we report that social contact increases, whereas isolation decreases, the mobilization of the endogenous marijuana-like neurotransmitter, anandamide, in the mouse nucleus accumbens (NAc), a brain structure that regulates motivated behavior. Pharmacological and genetic experiments show that anandamide mobilization and consequent activation of CB1 cannabinoid receptors are necessary and sufficient to express the rewarding properties of social interactions, assessed using a socially conditioned place preference test. We further show that oxytocin, a neuropeptide that reinforces parental and social bonding, drives anandamide mobilization in the NAc. Pharmacological blockade of oxytocin receptors stops this response, whereas chemogenetic, site-selective activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus stimulates it. Genetic or pharmacological interruption of anandamide degradation offsets the effects of oxytocin receptor blockade on both social place preference and cFos expression in the NAc. The results indicate that anandamide-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward. Deficits in this signaling mechanism may contribute to social impairment in autism spectrum disorders and might offer an avenue to treat these conditions. more...
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- 2015
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23. Your genes are conspiring against you
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Olga Peñagarikano
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0301 basic medicine ,Genetics ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Schizophrenia ,Dopamine receptor D2 ,medicine ,General Medicine ,Biology ,medicine.disease ,Gene ,030217 neurology & neurosurgery - Abstract
Gene variants in the dopamine receptor D2 expression network predict physiological and clinical features as well as treatment responses in schizophrenia.
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- 2017
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24. Building Bridges through Science
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Juan Carlos Gómez-Esteban, Helmut Kettenmann, Edmond H. Fischer, Serafim Rodrigues, John P. Adelman, Detlev Ganten, Sherif F. El-Khamisy, Shoji Komai, Agnès Gruart, Ashraf H. Badawi, S. Ather Enam, Atta-ur Rahman, Yasunori Hayashi, Andreas Draguhn, José L. Zugaza, Mohamed Jaber, Mustafa al'Absi, Mohammed Akaaboune, Jimena Baleriola, Hollis T. Cline, Thomas Lissek, Luis Martinez-Millan, Tiago F. Outeiro, Nouria Lakhdar Ghazal, Nikhat Ahmed Siddiqui, John E. Dowling, Erwin Neher, Karoly Nikolich, Joshua R. Sanes, Paul Young, Roger Guillemin, Ahmed A. Moustafa, Pedro Ramos-Cabrer, John F. Disterhoft, Craig Weiss, Michelle M. Adams, Mouna Maroun, José M. Delgado-García, Mario Treviño, Cathy C. Chang, Nasser H. Zawia, Tansu Celikel, Anwar Nasim, Ilaria Bertocchi, Carlos Belmonte, Kellie Dean, Andreas T. Schaefer, Hilmar Bading, Donald W. Pfaff, Bruno Poucet, José A. Esteban, Nils Brose, Reinhardt Jahn, Basim M. Uthman, Menahem Segal, Juan M. Encinas, Heinrich Betz, Ta Yuan Chang, Greg J. Stuart, Matthew E. Larkum, Patrizia Campolongo, Paolo Bonifazi, Larry J. Young, Olga Peñagarikano, Mathieu Desroches, Ofer Yizhar, Valery Grinevich, Merel Kindt, Abdeljabbar El Manira, J. Craig Venter, Richard J. Roberts, Hermona Soreq, Kathleen E. Cullen, Idan Segev, Saad Shafqat, Alexei Verkhratsky, Tobias Bonhoeffer, Adnan Abdul Jabbar, Mickey London, Torsten N. Wiesel, Jan Tønnesen, Asier Erramuzpe, Georg Köhr, Mohamed Kabbaj, Juan Carlos Arango-Lasprilla, Paul Greengard, Ali Rashidy-Pour, Beat Lutz, Albert Gidon, Abdul Mannan Baig, Michael Häusser, Ami Citri, Fazal Manzoor Arain, Mazahir T. Hasan, Iñigo Gabilondo, Olaf Blanke, Izumi Fukunaga, Emre Yaksi, Lucy M. Palmer, Ahmad R. Hariri, Bernd Kuhn, Isabel Fariñas, Huda Akil, Harm J. Krugers, Philipp Boehm-Sturm, Klaus-Armin Nave, Essam M. Janahi, Thomas C. Südhof, Ehud Ahissar, Colin Blakemore, Jesús Avila, Deniz Atasoy, Bassem A. Hassan, Shira Knafo, Eduardo Soriano-García, Isabel Pérez-Otaño, James L. McGaugh, Natasha K. Hussain, Rainer Spanagel, Carlos Matute, Rolf Sprengel, and Jesus M. Cortes more...
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History ,history 15th century ,history 21st century ,history medieval ,International Cooperation ,Neurophysiology ,Europe ,history ancient ,humans ,middle east ,neurosciences ,international cooperation ,neuroscience (all) ,Bridge (interpersonal) ,History, 21st Century ,Ancient ,03 medical and health sciences ,Middle East ,0302 clinical medicine ,Political science ,Humans ,Through Science ,History, Ancient ,History, 15th Century ,History, Medieval ,Neurosciences ,Neuroscience (all) ,General Neuroscience ,Building Bridges ,21st Century ,030227 psychiatry ,3. Good health ,15th Century ,General partnership ,Engineering ethics ,030217 neurology & neurosurgery ,Medieval - Abstract
WOS: 000415310800007 PubMed ID: 29144972 Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge'' initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities. Medical Research Council [MC_UP_1202/5] more...
- Published
- 2017
25. Stress: A deadly weapon
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Olga Peñagarikano
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Mitochondrial DNA ,Cell ,Suicide, Attempted ,General Medicine ,Biology ,Mitochondrion ,DNA, Mitochondrial ,Cell biology ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,medicine ,Humans ,Original Article ,Gene ,Stress, Psychological ,DNA - Abstract
Preclinical data suggest that chronic stress may cause cellular damage and mitochondrial dysfunction, potentially leading to the release of mitochondrial DNA (mtDNA) into the bloodstream. Major depressive disorder has been associated with an increased amount of mtDNA in leukocytes from saliva samples and blood; however, no previous studies have measured plasma levels of free-circulating mtDNA in a clinical psychiatric sample. In this study, free circulating mtDNA was quantified in plasma samples from 37 suicide attempters, who had undergone a dexamethasone suppression test (DST), and 37 healthy controls. We hypothesized that free circulating mtDNA would be elevated in the suicide attempters and would be associated with hypothalamic–pituitary–adrenal (HPA)-axis hyperactivity. Suicide attempters had significantly higher plasma levels of free-circulating mtDNA compared with healthy controls at different time points (pre- and post-DST; all P-values more...
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- 2016
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26. On antidepressants and still feeling low
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Olga Peñagarikano
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medicine.medical_specialty ,Sertraline ,business.industry ,media_common.quotation_subject ,Venlafaxine ,General Medicine ,Affect (psychology) ,Amygdala ,Neglect ,medicine.anatomical_structure ,medicine ,Antidepressant ,Escitalopram ,Psychiatry ,business ,Depression (differential diagnoses) ,medicine.drug ,media_common - Abstract
For some patients, antidepressants are a godsend. However, up to 30% of people on antidepressants do not show the expected favorable response. Because noticeable improvements from antidepressant therapy can take weeks or even months to manifest, markers or events that predict which patients will be responders and which will be nonresponders could speed therapy by preempting the delay before stopping medication and initiating trial of a new type of intervention. Now , Goldstein-Piekarski and collaborators use two factors that previously were independently associated with the development of depression—the presence of a childhood trauma and activation of the amygdala in response to emotional stimuli—to predict, with 80% accuracy, whether an antidepressant will help a patient recover from depression. It is well known that people who were exposed to early-life stress, such as abuse or neglect, are more prone to suffering from depression later in life. Although the neurobiological mechanism for this association is unknown, a potential explanation is that stress hormones released during early stressful events affect the development and function of a brain structure that plays a seminal role in the processing of emotions: the amygdala. In fact, depressed patients often display abnormal amygdala engagement upon exposure to different emotional stimuli. In the new work, the authors analyzed, by functional magnetic resonance imaging (fMRI), amygdala reactivity to rewarding stimuli (happy faces), adverse stimuli (fearful faces), or both in 70 individuals before and after an 8-week trial with three commonly used antidepressants: sertraline, escitalopram, and venlafaxine. They then correlated the fMRI data with early-life stress history in an attempt to predict improvement in depression symptoms. The correlated data suggested associations between a positive response to antidepressants and either low early-life stress exposure and amygdala hyporeactivity to both, rewarding and adverse cues or high early-life stress exposure and amygdala reactivity to rewarding cues. A routine fMRI scan for all patients with depression is unlikely. But identifying which patients might benefit the most from a drug—perhaps beginning with those who experienced high early-life stress—might save valuable months of nonresponse treatment for people with depression, which can be a life-threatening condition. A. N. Goldstein-Piekarski et al ., Human amygdala engagement moderated by early life stress exposure is a biobehavioral target for predicting recovery on antidepressants. Proc. Natl. Acad. Sci. U.S.A . 113 , 11955–11960 (2016). [[Full Text]][1] [1]: http://www.pnas.org/content/113/42/11955.full.pdf?with-ds=yes more...
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- 2016
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27. Money doesn’t bring happiness.... Or does it?
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Olga Peñagarikano
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Social stress ,Child psychopathology ,medicine ,Psychological intervention ,Anxiety ,General Medicine ,Environmental exposure ,medicine.symptom ,Child Behavior Checklist ,Psychology ,Socioeconomic status ,Clinical psychology ,Psychopathology - Abstract
Low socioeconomic status as assessed by income, education, and occupation is widely considered a risk factor for a broad range of health problems, including the development of neuropsychiatric disorders. Although this connection is well documented, research into the biological mechanisms that might underlie this association has been stymied by the complexity of the environmental factors associated with low socioeconomic status, such as toxic environmental exposure, social stress (isolation or defeat), poor lifestyle, and material deprivation. Research into the biological signature of psychopathological traits has identified alterations in the expression of several peripheral blood markers, including neurotrophic proteins (growth factors necessary for neuron development and survival) and proteins involved in inflammatory and oxidative processes. Now, Mansur et al. bridge the gap between these associations by showing that low socioeconomic status provides a link between peripheral blood markers and childhood psychopathology. The authors obtained blood samples for marker assessment as well as behavioral data measured with the Child Behavior Checklist (a standardized measurement of maladaptive and emotional behavior) in 495 children ages 4 to 18 and measured the interaction of these parameters with socioeconomic status. They found that low socioeconomic status was positively associated with both psychopathological behavioral traits and altered biological marker expression. In addition, analysis of the interactions among these three factors showed that the correlation of psychopathological traits with marker expression was higher in children with low socioeconomic status for all behaviors analyzed, including anxiety, depression, conduct problems, aggressive behavior, and inattention. Interestingly, the effect of low socioeconomic status seemed to be very specific in some instances, such as in the association of neurotrophic markers with the depressive behavioral scale, which was significant in children with low socioeconomic status compared with children with normal socioeconomic status. Although a longitudinal evaluation of this cohort would be needed to ascertain the causative role of these factors in the development of neuropsychiatric disorders, this work highlights an important role for low socioeconomic status in modulating the biological and behavioral expression of pathological behavioral traits. Also, studying the different dimensions of low socioeconomic status separately would provide insight into their relative contributions to psychiatric disorders that may have important implications for behavioral-based interventions. R. B. Mansur et al. , Socioeconomic disadvantage moderates the association between peripheral biomarkers and childhood psychopathology. PLOS ONE 11 , e0160455 (2016). [[Full Text]][1] [1]: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160455 more...
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- 2016
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28. Has the tooth fairy entered the realm of science?
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Olga Peñagarikano
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stomatognathic diseases ,History ,stomatognathic system ,Aesthetics ,Realm ,General Medicine ,Value (mathematics) ,The Imaginary - Abstract
The extended culture of keeping a child’s fallen baby teeth to be collected by imaginary figures such as the “tooth fairy” might turn out to be of scientific value. In recent work, Modabbernia et al. used baby teeth to track a person’s prenatal and infant exposure to metals and then more...
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- 2016
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29. Oxytocin in animal models of autism spectrum disorder
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Olga, Peñagarikano
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Disease Models, Animal ,Autism Spectrum Disorder ,Animals ,Humans ,Oxytocin ,Social Behavior - Abstract
Autism spectrum disorder is a behavioral disorder characterized by impairments in social interaction and communication together with the presence of stereotyped behaviors and restricted interests. Although highly genetic, its etiology is complex which correlates with the extensive heterogeneity found in its clinical manifestation, adding to the challenge of understanding its pathophysiology and develop targeted pharmacotherapies. The neuropeptide oxytocin is part of a highly conserved system involved in the regulation of social behavior, and both animal and human research have shown that variation in the oxytocin system accounts for interindividual differences in the expression of social behaviors in mammals. In autism, recent studies in human patients and animal models are starting to reveal that alterations in the oxytocin system are more common than previously anticipated. Genetic variation in the key players involved in the system (i.e., oxytocin receptor, oxytocin, and CD38) has been found associated with autism in humans, and animal models of the disorder converge in an altered oxytocin system and/or dysfunction in oxytocin related biological processes. Furthermore, oxytocin administration exerts a behavioral and neurobiological response, and thus, the oxytocin system has become a promising potential therapeutical target for autism. Animal models represent a valuable tool to aid in the research into the potential therapeutic use of oxytocin. In this review, I aim to discuss the main findings related to oxytocin research in autism with a focus on findings in animal models. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 202-213, 2017. more...
- Published
- 2016
30. Size matters: A growth chart for the brain connectome
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Olga Peñagarikano
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Percentile ,Growth chart ,Connectome ,General Medicine ,Psychology ,Cartography - Abstract
Growth charts are a widely used tool to assess the development of children. A growth chart consists of a series of percentile curves representing data collected for characteristics such as height and weight at different ages that helps to identify potential developmental problems. Now, Kessler et al more...
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- 2016
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31. Can the past predict the future?
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Olga Peñagarikano
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medicine.medical_specialty ,Etiology ,medicine ,Autism ,General Medicine ,Biology ,Psychiatry ,medicine.disease - Abstract
The etiology of most neuropsychiatric disorders is increasingly accepted to be a combination of genetic and environmental factors. Among these, exposure to prenatal adverse environmental effects such as toxins, stress, or infection has been suggested to be risk factors for disorders such as autism more...
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- 2016
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32. List of Contributors
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Stephanie A. Barnes, Silvia Bassani, Àlex Bayés, Elizabeth Berry-Kravis, Luigi Boccuto, Thomas Bourgeron, Jamel Chelly, Bice Chini, Jérôme Ezan, Jozef Gecz, Valentina Gigliucci, Xiaohong Gong, Seth G.N. Grant, Anne Hoffmann, Claire Homan, Elaine Y. Hsiao, Guillaume Huguet, Lachlan Jolly, Eunjoon Kim, Peter C. Kind, Jaewon Ko, Janine M. Lamonica, Marianna Leonzino, Natalia V. Malkova, Carla Marini, Caterina Michetti, Caterina Montani, Mireille Montcouquiol, Maïté M. Moreau, Edoardo Moretto, Alysson Renato Muotri, Emily K. Osterweil, Maria Passafaro, Olga Peñagarikano, Alan K. Percy, Duyen Pham, Katy Phelan, Laura Ricceri, Yoann Saillour, Carlo Sala, Nathalie Sans, Sara Sarasua, Maria Luisa Scattoni, Michael J. Schmeisser, Charles E. Schwartz, Yiping Shen, Chuan Tan, Daniel C. Tarquinio, Sophie R. Thomson, Chiara Verpelli, Kazuhiro Yamakawa, and Zhaolan Zhou more...
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- 2016
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33. CNTNAP2 Mutations in Autism
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Olga Peñagarikano
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medicine.medical_specialty ,CNTNAP2 ,Genetic heterogeneity ,Epigenetics of autism ,medicine.disease ,Imaging data ,Autism spectrum disorder ,mental disorders ,medicine ,Medical genetics ,Autism ,Psychology ,Neuroscience ,Gene - Abstract
Autism spectrum disorders (ASDs) comprise a phenotypically and genetically heterogeneous condition characterized by deficits in social behavior and communication together with the presence of repetitive and restrictive behaviors. Autism spectrum disorder has a strong genetic component and mutations/variants in many genes have been identified as predisposing to ASD. The contactin-associated protein-like 2 ( CNTNAP2 ) gene is one of the most replicated through interdisciplinary studies, supported by neurobiological, genetic, and imaging data. An understanding of the mechanistic link between genes and behavior is critical to developing targeted treatments. This chapter discusses the clinical genetics and current understanding of the biology of CNTNAP2 as related to ASD. Current multidisciplinary research approaches in both human subjects and animal models help us understand the pathophysiology associated with the goal of developing new treatments. more...
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- 2016
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34. What does CNTNAP2 reveal about autism spectrum disorder?
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Olga Peñagarikano and Daniel H. Geschwind
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medicine.medical_specialty ,CNTNAP2 ,Nerve Tissue Proteins ,Disease ,Language Development ,Article ,Mice ,mental disorders ,medicine ,Animals ,Humans ,Child ,Psychiatry ,Molecular Biology ,Human studies ,Genetic heterogeneity ,Mechanism (biology) ,Membrane Proteins ,medicine.disease ,Disease Models, Animal ,Language development ,Child Development Disorders, Pervasive ,Autism spectrum disorder ,Child, Preschool ,Molecular Medicine ,Medical genetics ,Neuroscience - Abstract
Autism spectrum disorder (ASD) is a phenotypically and genetically heterogeneous condition characterized by the presence of repetitive/restrictive behaviors and variable deficits in language and social behavior. Many genes predisposing an individual to ASD have been identified, and understanding the causal disease mechanism(s) is critical to be able to develop treatments. Neurobiological, genetic, and imaging data provide strong evidence for the CNTNAP2 gene as a risk factor for ASD and related neurodevelopmental disorders. This review discusses the clinical genetics and current understanding of the biology of CNTNAP2 as related to ASD and illustrates how the integration of multiple research approaches, from human studies to animal models, converge to inform functional biology focused on novel treatment development. more...
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- 2012
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35. Animal models guided drug discovery in autism: The case for oxytocin
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Olga Peñagarikano
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Oxytocin ,Drug discovery ,business.industry ,Applied Mathematics ,General Mathematics ,medicine ,Autism ,medicine.disease ,business ,Neuroscience ,medicine.drug - Published
- 2018
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36. Path to understanding the pathophysiology of Fragile X syndrome
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Stephen T. Warren, Jennifer G. Mulle, and Olga Peñagarikano
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Genetics ,Molecular pathology ,Disease ,Biology ,medicine.disease ,Bioinformatics ,Pathophysiology ,Premature ovarian failure ,Fragile X syndrome ,Clinical research ,Neurology ,Intervention (counseling) ,medicine ,Identification (biology) ,Neurology (clinical) - Abstract
The goal of all clinical research is to abolish suffering caused by human disease. This can be achieved by the development of suitable intervention, be it treatment, prevention or cure. If the cellular or molecular pathology underlying a specific disease process is understood, therapeutic intervention may be more rapidly realized. For disease where a fraction of the risk is heritable, genetic analysis can be a key strategy: the identification of a genetic variant and subsequent aberrant protein that causes disease lends insight to pathology and subsequent treatment alternatives. One example of this is Fragile X syndrome, where the discovery of the causative gene enabled dissection of the molecular pathway that is disrupted in affected individuals. In this review, we will describe this path to understanding, from discovery of the gene to the current model of disease. more...
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- 2007
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37. Cerebellar associative sensory learning defects in five mouse autism models
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Andrea Giovannucci, Olga Peñagarikano, Claire Piochon, Sara G Connolly, Amy Li, Giorgio Grasselli, Alexander D. Kloth, Samuel S.-H. Wang, Toru Takumi, Paul F. Worley, Mustafa Sahin, Peter T. Tsai, Christian Hansel, M. Ali Ali Bangash, Daniel H. Geschwind, Adriana Cherskov, and Aleksandra Badura more...
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Cerebellum ,genetic structures ,Autism ,associative learning ,neuroscience ,Purkinje Cells ,Mice ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Biology (General) ,Aetiology ,Pediatric ,0303 health sciences ,General Neuroscience ,General Medicine ,Anticipation ,Conditioning, Eyelid ,medicine.anatomical_structure ,Mental Health ,Eyeblink conditioning ,Autism spectrum disorder ,Medicine ,Psychology ,Research Article ,congenital, hereditary, and neonatal diseases and abnormalities ,cerebellum ,QH301-705.5 ,Science ,Intellectual and Developmental Disabilities (IDD) ,1.1 Normal biological development and functioning ,Sensory system ,autism spectrum disorder ,Affect (psychology) ,Basic Behavioral and Social Science ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Underpinning research ,Behavioral and Social Science ,medicine ,Genetics ,Animals ,Autistic Disorder ,mouse ,030304 developmental biology ,General Immunology and Microbiology ,Animal ,Neurosciences ,Association Learning ,medicine.disease ,Associative learning ,Brain Disorders ,Disease Models, Animal ,Eyelid ,Disease Models ,Biochemistry and Cell Biology ,Neuroscience ,030217 neurology & neurosurgery ,Conditioning - Abstract
Sensory integration difficulties have been reported in autism, but their underlying brain-circuit mechanisms are underexplored. Using five autism-related mouse models, Shank3+/ΔC, Mecp2R308/Y, Cntnap2−/−, L7-Tsc1 (L7/Pcp2Cre::Tsc1flox/+), and patDp(15q11-13)/+, we report specific perturbations in delay eyeblink conditioning, a form of associative sensory learning requiring cerebellar plasticity. By distinguishing perturbations in the probability and characteristics of learned responses, we found that probability was reduced in Cntnap2−/−, patDp(15q11-13)/+, and L7/Pcp2Cre::Tsc1flox/+, which are associated with Purkinje-cell/deep-nuclear gene expression, along with Shank3+/ΔC. Amplitudes were smaller in L7/Pcp2Cre::Tsc1flox/+ as well as Shank3+/ΔC and Mecp2R308/Y, which are associated with granule cell pathway expression. Shank3+/ΔC and Mecp2R308/Y also showed aberrant response timing and reduced Purkinje-cell dendritic spine density. Overall, our observations are potentially accounted for by defects in instructed learning in the olivocerebellar loop and response representation in the granule cell pathway. Our findings indicate that defects in associative temporal binding of sensory events are widespread in autism mouse models. DOI: http://dx.doi.org/10.7554/eLife.06085.001, eLife digest On a windy day, hearing the sound of wind makes many individuals squint in anticipation in order to protect their eyes. Linking two sensations that arrive within a split second of one another, such as sound and the feeling of wind, is a type of learning that requires the cerebellum, a region found at the base of the brain. When done in a laboratory setting, this particular form of learning has been dubbed eyeblink conditioning. Individuals with autism tend to have difficulties with appropriate matching of different senses. For example, they have trouble identifying a video that goes with a spoken soundtrack. They also do not learn eyeblink conditioning the same way that other individuals do. However, it is not known which circuits in the brain are responsible for their difficulty. Kloth et al. now investigate this issue by asking whether versions of genes that increase the risk of autism in humans also disrupt eyeblink conditioning in mice. They tested five types of mouse model, each with a different genetic mutation that has previously been linked to autism. All five of these mutations cause defects in different cell types of the cerebellum, and all mice have abnormal social and habitual behaviors, similar to autistic people. The tests involved shining a bright light at the mice, which was followed, a split second later, by a puff of air that always causes the mice to blink. After this had occurred dozens of times, the mice started to blink earlier, as soon as the light appeared, in anticipation of the puff of air. To test whether the mice had successfully learned to respond to just the bright light, the light was also occasionally flashed without a puff of air. Kloth et al. found that the mice generally performed poorly in eyeblink conditioning, although in different ways depending on which cell types of the cerebellum were affected by the genetic mutations. Some mice blinked too soon or too late after the light appeared; others blinked weakly or less frequently; and some did not blink at all. This suggests that autism can affect the processing of sensory information in the cerebellum in different ways. This work is important because it demonstrates that a form of split-second multisensory learning is generally disrupted by autism genes. If defects in cerebellar learning are present early in life, they could keep autistic children from learning about the world around them, and drive their developing brains off track. Hundreds of autism genes have been found. Linking these genes to a single brain region identifies the cerebellum as an important anatomical target for future diagnosis and intervention. DOI: http://dx.doi.org/10.7554/eLife.06085.002 more...
- Published
- 2015
38. VoICE: A semi-automated pipeline for standardizing vocal analysis across models
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Zachary D. Burkett, Nancy F. Day, Olga Peñagarikano, Daniel H. Geschwind, and Stephanie A. White
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Vocal communication ,Computer science ,Intellectual and Developmental Disabilities (IDD) ,Knockout ,Autism ,Speech recognition ,Nerve Tissue Proteins ,Inbred C57BL ,Basic Behavioral and Social Science ,Article ,Speech Acoustics ,Session (web analytics) ,Vocalization ,Mice ,Automation ,03 medical and health sciences ,0302 clinical medicine ,Behavioral and Social Science ,Animals ,Cluster Analysis ,Intellectual and Developmental Disabilities ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,Animal ,Repertoire ,Membrane Proteins ,Pipeline (software) ,Brain Disorders ,Mice, Inbred C57BL ,Other Physical Sciences ,Phenotype ,Mental Health ,Vocal learning ,Finches ,Biochemistry and Cell Biology ,Vocalization, Animal ,030217 neurology & neurosurgery - Abstract
The study of vocal communication in animal models provides key insight to the neurogenetic basis for speech and communication disorders. Current methods for vocal analysis suffer from a lack of standardization, creating ambiguity in cross-laboratory and cross-species comparisons. Here, we present VoICE (Vocal Inventory Clustering Engine), an approach to grouping vocal elements by creating a high dimensionality dataset through scoring spectral similarity between all vocalizations within a recording session. This dataset is then subjected to hierarchical clustering, generating a dendrogram that is pruned into meaningful vocalization “types” by an automated algorithm. When applied to birdsong, a key model for vocal learning, VoICE captures the known deterioration in acoustic properties that follows deafening, including altered sequencing. In a mammalian neurodevelopmental model, we uncover a reduced vocal repertoire of mice lacking the autism susceptibility gene, Cntnap2. VoICE will be useful to the scientific community as it can standardize vocalization analyses across species and laboratories. more...
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- 2015
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39. Author response: Cerebellar associative sensory learning defects in five mouse autism models
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Christian Hansel, Samuel S.-H. Wang, Andrea Giovannucci, Aleksandra Badura, Alexander D. Kloth, Mustafa Sahin, Claire Piochon, Sara G Connolly, Toru Takumi, Daniel H. Geschwind, Amy Li, M. Ali Ali Bangash, Paul F. Worley, Olga Peñagarikano, Giorgio Grasselli, Adriana Cherskov, and Peter T. Tsai more...
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medicine ,Autism ,Sensory system ,Psychology ,medicine.disease ,Neuroscience ,Associative property - Published
- 2015
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40. The emerging picture of autism spectrum disorder: genetics and pathology
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Daniel H. Geschwind, T. Grant Belgard, Jason A. Chen, Vivek Swarup, and Olga Peñagarikano
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Pathology ,medicine.medical_specialty ,Molecular pathology ,Systems biology ,Disease mechanisms ,Neuropathology ,Biology ,medicine.disease ,behavioral disciplines and activities ,Human genetics ,Social relation ,Pathology and Forensic Medicine ,Disease Models, Animal ,Mice ,Autism spectrum disorder ,Child Development Disorders, Pervasive ,mental disorders ,medicine ,Animals ,Humans ,Heterogeneous disorder - Abstract
Autism spectrum disorder (ASD) is defined by impaired social interaction and communication accompanied by stereotyped behaviors and restricted interests. Although ASD is common, its genetic and clinical features are highly heterogeneous. A number of recent breakthroughs have dramatically advanced our understanding of ASD from the standpoint of human genetics and neuropathology. These studies highlight the period of fetal development and the processes of chromatin structure, synaptic function, and neuron-glial signaling. The initial efforts to systematically integrate findings of multiple levels of genomic data and studies of mouse models have yielded new clues regarding ASD pathophysiology. This early work points to an emerging convergence of disease mechanisms in this complex and etiologically heterogeneous disorder. more...
- Published
- 2015
41. The Autism Related Protein Contactin-Associated Protein-Like 2 (CNTNAP2) Stabilizes New Spines: An In Vivo Mouse Study
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Joshua T. Trachtenberg, Olga Peñagarikano, Maria T. Lazaro, Amos Gdalyahu, Daniel H. Geschwind, Peyman Golshani, and Dunaevsky, Anna
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Male ,CNTNAP2 ,Dendritic spine ,General Science & Technology ,Intellectual and Developmental Disabilities (IDD) ,Autism ,1.1 Normal biological development and functioning ,Dendritic Spines ,lcsh:Medicine ,Nerve Tissue Proteins ,Biology ,Bioinformatics ,Basic Behavioral and Social Science ,Mice ,In vivo ,Underpinning research ,Behavioral and Social Science ,medicine ,Animals ,lcsh:Science ,Multidisciplinary ,Prevention ,lcsh:R ,Neurosciences ,Membrane Proteins ,medicine.disease ,Cell biology ,Brain Disorders ,Spine (zoology) ,Mental Health ,Membrane protein ,Neuronal circuits ,Female ,lcsh:Q ,Research Article ,CONTACTIN-ASSOCIATED PROTEIN - Abstract
The establishment and maintenance of neuronal circuits depends on tight regulation of synaptic contacts. We hypothesized that CNTNAP2, a protein associated with autism, would play a key role in this process. Indeed, we found that new dendritic spines in mice lacking CNTNAP2 were formed at normal rates, but failed to stabilize. Notably, rates of spine elimination were unaltered, suggesting a specific role for CNTNAP2 in stabilizing new synaptic circuitry. more...
- Published
- 2015
42. Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism
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Olga Peñagarikano, Hoa A. Lam, Nigel T. Maidment, Aaron Gordon, Xiao-Hong Lu, Hongmei Dong, Niall P. Murphy, X. William Yang, Daniel H. Geschwind, Maria T. Lazaro, Elior Peles, and Peyman Golshani
- Subjects
Autism ,Oxytocin ,Medical and Health Sciences ,Oxytocin Antagonist ,Mice ,2.1 Biological and endogenous factors ,Aetiology ,Mice, Knockout ,Neurons ,Pediatric ,Behavior, Animal ,General Medicine ,Biological Sciences ,Melanocortin 4 receptor ,Mutant Strains ,Mental Health ,Hypothalamus ,5.1 Pharmaceuticals ,Knockout mouse ,Neurological ,Development of treatments and therapeutic interventions ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Agonist ,medicine.medical_specialty ,endocrine system ,medicine.drug_class ,Knockout ,Intellectual and Developmental Disabilities (IDD) ,1.1 Normal biological development and functioning ,Neuropeptide ,Nerve Tissue Proteins ,Basic Behavioral and Social Science ,Article ,Underpinning research ,Internal medicine ,Behavioral and Social Science ,medicine ,Genetics ,Animals ,Humans ,Autistic Disorder ,Social Behavior ,Behavior ,business.industry ,Animal ,Neurosciences ,Membrane Proteins ,Cortical dysplasia ,medicine.disease ,Newborn ,Mice, Mutant Strains ,Brain Disorders ,Disease Models, Animal ,Endocrinology ,Animals, Newborn ,Disease Models ,business ,Paraventricular Hypothalamic Nucleus - Abstract
Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homolog of CNTNAP2 (contactin-associated protein-like 2), in which mutations cause cortical dysplasia and focal epilepsy (CDFE) syndrome, displays many features that parallel those of the human disorder. Because CDFE has high penetrance for autism spectrum disorder (ASD), we performed an in vivo screen for drugs that ameliorate abnormal social behavior in Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in Cntnap2 knockout mice and suggest that there may be critical developmental windows for optimal treatment to rectify this deficit. more...
- Published
- 2015
43. A new insight into fragile X syndrome among Basque population
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A. Gil, Begoña Criado, Olga Peñagarikano, Isabel Arrieta, Mercedes Télez, Ana Peixoto, Isabel Veiga, Begoña Ortega, and Piedad Flores
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Genetics ,education.field_of_study ,Population ,Haplotype ,Biology ,medicine.disease ,FMR1 ,Fragile X syndrome ,medicine ,Allele ,education ,Trinucleotide repeat expansion ,Genetics (clinical) ,X chromosome ,Sequence (medicine) - Abstract
The expansion of a trinucleotide repeat [CGG]n located in the FMR1 X-linked gene is the main cause of fragile X syndrome, the most common form of inherited mental retardation. We have analyzed the factors known, to date, to influence the instability of the repeat in 158 normal X chromosomes from the Spanish Basque population. These factors included length of the repeat, AGG interspersion pattern, length of uninterrupted CGG and DXS548-FRAXAC1 markers associated haplotype. Previous investigations on Basques showed an absence of this disorder among mentally retarded individuals that was likely due to a low prevalence of large CGG alleles and the presence of AGG interruptions on them. The present report suggests that, although the frequency of large alleles is low and they do maintain AGG interruptions, different mutational pathways that might lead to fragile X syndrome could be occurring among Basques. These pathways mainly include alleles with internal sequences 9 + 9 + n and 9 + 12 + 9 that show fragile X associated haplotypes. Besides, the lack of the most proximal AGG interruption, proposed recently as a novel factor involved in CGG repeat instability, was highly identified among alleles with long pure CGG tracts, which showed an internal sequence n + 9. The data suggest that, despite the lower incidence of large alleles, the prevalence of potentially unstable alleles among Basques is similar to that of other Caucasian populations and that these alleles could become fragile X chromosomes. more...
- Published
- 2004
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44. CNTNAP2 and Autism Spectrum Disorders
- Author
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Olga Peñagarikano and Daniel H. Geschwind
- Subjects
mental disorders - Abstract
Although autism was described in the early 1940s as a disorder of affective contact (Kanner, 1943), it was not classified as a neurodevelopmental disorder with a biological basis until the early 1980s, when studies reported its high heritability (Folstein & Rutter, 1977; Ritvo et al., 1985) and co-occurrence with chromosomal abnormalities (Gillberg & Wahlstrom, 1985; Wahlström et al., 1986). Today, autism is considered a heterogeneous neurodevelopmental syndrome and therefore termed autism spectrum disorder (ASD), characterized by variable deficits in social behavior and language, restrictive interests, and repetitive behaviors. Autism spectrum disorder has an estimated prevalence of 1:150–1:200 (Centers for Disease Control and Prevention, 2007), being one of the most common childhood disorders. In addition to the core domains necessary for diagnosis, a number of other behavioral abnormalities are frequently associated with ASD, including epilepsy, sensory abnormalities, hyperactivity, motor abnormalities, sleep disturbances, and gastrointestinal symptoms (Geschwind, 2009). more...
- Published
- 2013
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45. 3D visualization of the regional differences
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David R. Hampson, Toru Takumi, Christopher L. Muller, Elaine Tam, M. C. van Eede, Daniel H. Geschwind, Nobuhiro Nakai, Alea A. Mills, Zhong Xuan, F. Espinosa-Becerra, Jeremy Veenstra-VanderWeele, Lucy R. Osborne, R. M. Henkelman, Jacqueline N. Crawley, Emanuel DiCicco-Bloom, Laura K. K. Pacey, Travis M. Kerr, Jin Nakatani, Jason P. Lerch, Olga Peñagarikano, Jonathan Lai, Craig M. Powell, Jane A. Foster, Brooke A. Babineau, Diane M. Robins, C. L. Laliberté, Evdokia Anagnostou, Lulu Lin, Jacob Ellegood, Matthieu Genestine, Mehreen Kouser, Randy D. Blakely, and Armin Raznahan more...
- Subjects
Group (mathematics) ,Brain ,Neuroimaging ,Anatomy ,Biology ,medicine.disease ,Article ,Developmental psychology ,Mice ,Cellular and Molecular Neuroscience ,Psychiatry and Mental health ,Imaging, Three-Dimensional ,medicine ,Animals ,Autism ,Molecular Biology ,Regional differences - Abstract
We examined 26 different mouse models related to autism and identified three groups that shared similar neuroanatomical phenotypes. These three groups and their regional differences are shown here. Anything highlighted in red was determined to be larger in that group (median effect size for group >0.5) and anything highlighted in blue was determined to be smaller in that group (median effect size for group < − 0.5). These differences are shown in 3D in an axial representation either looking from above (a) or below (b) the mouse brain. For more information on this topic, please refer to the article by Ellegood et al on pages 118–125. more...
- Published
- 2015
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46. A new insight into fragile X syndrome among Basque population
- Author
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Olga, Peñagarikano, Alberto, Gil, Mercedes, Télez, Begoña, Ortega, Piedad, Flores, Isabel, Veiga, Ana, Peixoto, Begoña, Criado, and Isabel, Arrieta
- Subjects
Genetic Markers ,Male ,Genetics, Population ,Polymorphism, Genetic ,Gene Frequency ,Haplotypes ,Fragile X Syndrome ,Humans ,Genetic Testing ,Trinucleotide Repeat Expansion ,White People - Abstract
The expansion of a trinucleotide repeat [CGG]n located in the FMR1 X-linked gene is the main cause of fragile X syndrome, the most common form of inherited mental retardation. We have analyzed the factors known, to date, to influence the instability of the repeat in 158 normal X chromosomes from the Spanish Basque population. These factors included length of the repeat, AGG interspersion pattern, length of uninterrupted CGG and DXS548-FRAXAC1 markers associated haplotype. Previous investigations on Basques showed an absence of this disorder among mentally retarded individuals that was likely due to a low prevalence of large CGG alleles and the presence of AGG interruptions on them. The present report suggests that, although the frequency of large alleles is low and they do maintain AGG interruptions, different mutational pathways that might lead to fragile X syndrome could be occurring among Basques. These pathways mainly include alleles with internal sequences 9 + 9 + n and 9 + 12 + 9 that show fragile X associated haplotypes. Besides, the lack of the most proximal AGG interruption, proposed recently as a novel factor involved in CGG repeat instability, was highly identified among alleles with long pure CGG tracts, which showed an internal sequence n + 9. The data suggest that, despite the lower incidence of large alleles, the prevalence of potentially unstable alleles among Basques is similar to that of other Caucasian populations and that these alleles could become fragile X chromosomes. more...
- Published
- 2004
47. The FMR1 CGG repeat and linked microsatellite markers in two Basque valleys
- Author
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I Veiga, B. Criado, Begoña Ortega, A L Peixoto, Mercedes Télez, Isabel Arrieta, Piedad Flores, C. M. Lostao, and Olga Peñagarikano
- Subjects
Genetics ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,education.field_of_study ,Population ,Haplotype ,RNA-Binding Proteins ,Biology ,medicine.disease ,FMR1 ,Fragile X syndrome ,Gene Frequency ,Haplotypes ,Trinucleotide Repeats ,medicine ,Microsatellite ,Humans ,Allele ,education ,Allele frequency ,Genetics (clinical) ,X chromosome - Abstract
Fragile X syndrome is associated with an unstable CGG repeat sequence in the 5' untranslated region of the first exon of the FMR1 gene. The present study involved the evaluation of factors implicated in CGG repeat stability in a normal sample from two Basque valleys (Markina and Arratia), to discover whether the Basque population shows allelic diversity and to identify factors involved, by using the data in conjunction with previous findings. The study was based on a sample of 204 and 58 X chromosomes from the Markina and Arratia valleys, respectively. The CGG repeat, the AGG interspersion and two flanking microsatellite markers, FRAXAC1 and DXS548, were examined. In the Markina valley, gray zone alleles (> or =35 CGG repeats) were associated with anchoring AGGs, with the longest 3' pure CGG repeats of the valley (=15), with the 5' instability structure 9+n and with one principal fragile X FRAXAC1-DXS548 haplotype 42-50. In the Arratia valley, gray zone alleles (> or =35 CGG repeats) showed the highest frequency among the Basque samples analyzed, and were associated with anchoring AGGs, with the longest 3' pure repeats (> or =20), with the 5' instability structure 9+n and with one "normal" FRAXAC1-DXS548 haplotype 38-40 (these data from Arratia suggest the existence of a "protective" haplotype). The results showed, on the one hand, differences between Markina and Arratia in factors implicated in CGG repeat instability and, on the other hand, a great similarity between the general Basque sample from Biscay and the Markina valley. more...
- Published
- 2003
48. Erratum: What does CNTNAP2 reveal about autism spectrum disorder?
- Author
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Daniel H. Geschwind and Olga Peñagarikano
- Subjects
Genetics ,CNTNAP2 ,business.industry ,medicine.disease ,Autism spectrum disorder ,Molecular Medicine ,Medicine ,Autism ,medicine.symptom ,business ,Molecular Biology ,Exome sequencing ,De novo mutations ,Confusion - Abstract
We regret that two errors have occurred in this paper. First, owing to a typographical error in the original reference, Table 1, line 3 incorrectly lists the mutation H275A. This should be H275R. Please see [1xExome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. O’Roak, B.J. et al. Nat. Genet. 2011; 43: 585–589CrossRef | PubMed | Scopus (422)See all References][1] and [2xCorrigendum: Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. O’Roak, B.J. et al. Nat. Genet. 2012; 44: 471CrossRef | Scopus (9)See all References][2] for more information.In addition, citation number [19] for O’Roak et al. (reference [1xExome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. O’Roak, B.J. et al. Nat. Genet. 2011; 43: 585–589CrossRef | PubMed | Scopus (422)See all References][1] below) listed an incorrect volume number. The correct volume is 43. The authors and editors apologize for any confusion. more...
- Published
- 2012
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49. Absence of CNTNAP2 Leads to Epilepsy, Neuronal Migration Abnormalities, and Core Autism-Related Deficits
- Author
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Brett S. Abrahams, Edward I. Herman, Hongmei Dong, Daniel H. Geschwind, Peyman Golshani, Joel Almajano, Joshua T. Trachtenberg, Kellen D. Winden, Lisa I. Sonnenblick, Robin Gruver, Amos Gdalyahu, Elior Peles, Anatol Bragin, and Olga Peñagarikano more...
- Subjects
CNTNAP2 ,Mutant ,Nerve Tissue Proteins ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Cell Movement ,Interneurons ,mental disorders ,medicine ,Biological neural network ,Animals ,Humans ,Autistic Disorder ,Gene ,030304 developmental biology ,Mice, Knockout ,Neurons ,0303 health sciences ,Risperidone ,Biochemistry, Genetics and Molecular Biology(all) ,Brain ,Membrane Proteins ,medicine.disease ,Disease Models, Animal ,Autism ,Neuronal Migration Abnormalities ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
SummaryAlthough many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here, we characterize a mouse knockout of the Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. Cntnap2−/− mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as have been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity. In addition, treatment with the FDA-approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.PaperFlick more...
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50. JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse
- Author
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Daniel H. Geschwind, Changhoon Lee, Eric Tam, Elyse P. Kite, Stephanie A. White, Laurie Galvan, Carlos Cepeda, Jeremy A. Miller, Jason L. Stein, Jane Y. Chen, Zachary D. Burkett, Asami Oguro-Ando, Alvin Li, Jamee M. Berg, James A. Wohlschlegel, Leslie Chen, Mary E. Starks, Scott C. Fears, Ajay A. Vashisht, Olga Peñagarikano, Michael S. Levine, Amos Gdalyahu, Noor B. Al-Sharif, Department of Chemistry, North Carolina Raleigh, North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), Center for Neurobehavioral Genetics, Semel Institute, and University of California more...
- Subjects
Male ,Proteomics ,Autism Spectrum Disorder ,Autism ,Synaptogenesis ,RNA-binding protein ,Inbred C57BL ,Mice ,Neurodevelopmental disorder ,2.1 Biological and endogenous factors ,Psychology ,Gene Regulatory Networks ,ComputingMilieux_MISCELLANEOUS ,Pediatric ,Mice, Knockout ,Neurons ,General Neuroscience ,musculoskeletal, neural, and ocular physiology ,Adaptor Proteins ,RNA-Binding Proteins ,Translation (biology) ,Fragile X syndrome ,Mental Health ,Autism spectrum disorder ,Neurological ,Cognitive Sciences ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neural development ,psychological phenomena and processes ,Knockout ,Neuroscience(all) ,Biology ,behavioral disciplines and activities ,Rare Diseases ,Behavioral and Social Science ,mental disorders ,Genetics ,medicine ,Animals ,Intellectual and Developmental Disabilities ,Adaptor Proteins, Signal Transducing ,Neurology & Neurosurgery ,Signal Transducing ,Neurosciences ,medicine.disease ,Brain Disorders ,Mice, Inbred C57BL ,nervous system ,Fragile X Syndrome ,Protein Biosynthesis ,Synapses ,Janus kinase ,Neuroscience - Abstract
© 2015 Elsevier Inc. Autism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders. more...
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