title: Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits.
abstract: Although 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.
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Peñagarikano
authors.forename: Brett S
authors.initials: BS
authors.lastname: Abrahams
authors.forename: Edward I
authors.initials: EI
authors.lastname: Herman
authors.forename: Kellen D
authors.initials: KD
authors.lastname: Winden
authors.forename: Amos
authors.initials: A
authors.lastname: Gdalyahu
authors.forename: Hongmei
authors.initials: H
authors.lastname: Dong
authors.forename: Lisa I
authors.initials: LI
authors.lastname: Sonnenblick
authors.forename: Robin
authors.initials: R
authors.lastname: Gruver
authors.forename: Joel
authors.initials: J
authors.lastname: Almajano
authors.forename: Anatol
authors.initials: A
authors.lastname: Bragin
authors.forename: Peyman
authors.initials: P
authors.lastname: Golshani
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Trachtenberg
authors.forename: Elior
authors.initials: E
authors.lastname: Peles
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics; D006801:Humans; D007395:Interneurons / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000473:pathology
chemical_list: C403049:CNTNAP2 protein, human; C568163:CNTNAP2 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins