title: Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition.
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.
authors.affiliation: ADHD Clinical Research Unit, Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Rivero
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: Selten
authors.affiliation: ADHD Clinical Research Unit, Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Sich
authors.affiliation: ADHD Clinical Research Unit, Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Popp
authors.affiliation: ADHD Clinical Research Unit, Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bacmeister
authors.affiliation: Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Amendola
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Negwer
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Schubert
authors.affiliation: ADHD Clinical Research Unit, Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Proft
authors.affiliation: ADHD Clinical Research Unit, Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kiser
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: A G
authors.initials: AG
authors.lastname: Schmitt
authors.affiliation: Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Gross
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, the Netherlands.
authors.forename: S M
authors.initials: SM
authors.lastname: Kolk
authors.affiliation: Department of Translational Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Strekalova
authors.affiliation: Department of Translational Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: van den Hove
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, University Hospital Basel, University of Basel, Basel, Switzerland.
authors.forename: T J
authors.initials: TJ
authors.lastname: Resink
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Nadif Kasri
authors.affiliation: ADHD Clinical Research Unit, Division of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University of Würzburg, Würzburg, Germany.|Department of Translational Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors.forename: K P
authors.initials: KP
authors.lastname: Lesch
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics / Q000473:pathology / Q000523:psychology; D015820:Cadherins / Q000235:genetics; D004195:Disease Models, Animal; D016147:Genes, Tumor Suppressor; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007395:Interneurons / Q000502:physiology; D007858:Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D011599:Psychopathology; D009435:Synaptic Transmission / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D015820:Cadherins; C099972:H-cadherin; D005680:gamma-Aminobutyric Acid