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      Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition

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          Abstract

          Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13 −/− mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13 −/− mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.

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          Cortical inhibitory neurons and schizophrenia.

          Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (gamma-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.
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            Interneuron dysfunction in psychiatric disorders.

            Schizophrenia, autism and intellectual disabilities are best understood as spectrums of diseases that have broad sets of causes. However, it is becoming evident that these conditions also have overlapping phenotypes and genetics, which is suggestive of common deficits. In this context, the idea that the disruption of inhibitory circuits might be responsible for some of the clinical features of these disorders is gaining support. Recent studies in animal models demonstrate that the molecular basis of such disruption is linked to specific defects in the development and function of interneurons - the cells that are responsible for establishing inhibitory circuits in the brain. These insights are leading to a better understanding of the causes of schizophrenia, autism and intellectual disabilities, and may contribute to the development of more-effective therapeutic interventions.
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              A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells.

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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                October 2015
                13 October 2015
                1 October 2015
                : 5
                : 10
                : e655
                Affiliations
                [1 ]ADHD Clinical Research Unit, Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg , Würzburg, Germany
                [2 ]Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center , Nijmegen, the Netherlands
                [3 ]Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center , Nijmegen, the Netherlands
                [4 ]Mouse Biology Unit, European Molecular Biology Laboratory , Monterotondo, Italy
                [5 ]Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg , Würzburg, Germany
                [6 ]Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen , Nijmegen, the Netherlands
                [7 ]Department of Translational Neuroscience, School for Mental Health and Neuroscience, Maastricht University , Maastricht, the Netherlands
                [8 ]Department of Biomedicine, Laboratory for Signal Transduction, University Hospital Basel, University of Basel , Basel, Switzerland
                Author notes
                [* ]ADHD Clinical Research Unit, Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg , Füchsleinstrasse 15, 97080 Würzburg, Germany. E-mail: kplesch@ 123456mail.uni-wuerzburg.de
                [9]

                These authors contributed equally to this work.

                [10]

                Equal principal investigator contribution.

                Article
                tp2015152
                10.1038/tp.2015.152
                4930129
                26460479
                94f99a22-d0cb-4be1-871a-498cefd2c4ad
                Copyright © 2015 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 07 July 2015
                : 11 July 2015
                Categories
                Original Article

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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