TY - JOUR
T1 - Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits
AU - Penagarikano, Olga
AU - Abrahams, Brett S.
AU - Herman, Edward I.
AU - Winden, Kellen D.
AU - Gdalyahu, Amos
AU - Dong, Hongmei
AU - Sonnenblick, Lisa I.
AU - Gruver, Robin
AU - Almajano, Joel
AU - Bragin, Anatol
AU - Golshani, Peyman
AU - Trachtenberg, Joshua T.
AU - Peles, Elior
AU - Geschwind, Daniel H.
N1 - NIH/NIMH [R01 MH081754-02R]; NIH ACE Center [1P50-HD055784-01, 5R01-MH081754-04]; NIH [NS50220]; Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Incumbent of the Hanna Hertz Professorial Chair for Multiple Sclerosis and NeuroscienceWe thank the UCLA behavioral testing core and its supervisor, Dr. Ravi Ponnusamy, for assistance with behavioral testing. We also thank Dr. Alcino Silva, codirector of the core, for his critical discussions about mouse behavioral testing; Dr. Stephanie White for the UsV equipment and software; Dr. Carolyn Houser for assistance with GAD1 IHC; and Dr. William Yang and Dr. Istvan Mody for helpful discussions. We would also like to thank Jamee Bomar and Dr. Asami Oguro-Ando for help with floating IHC and helpful discussions; Greg Osborn for help with UsV analysis; Clark Rosensweig for help with mouse genotyping; Dr. Irina Voineagu and Lauren Kawaguchi for critically reading the manuscript; and Dr. Eric Wexler for useful discussions on drug treatment. This work was supported by grants NIH/NIMH R01 MH081754-02R to D.H.G.; NIH ACE Center 1P50-HD055784-01 to D.H.G. (Project II) and Network grant 5R01-MH081754-04 to D. H. G.; NIH/NS50220 to E.P.; and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to D.H.G. and E.P.E.P. is the Incumbent of the Hanna Hertz Professorial Chair for Multiple Sclerosis and Neuroscience.
PY - 2011/9/30
Y1 - 2011/9/30
N2 - 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. PaperFlick:
AB - 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. PaperFlick:
UR - http://www.scopus.com/inward/record.url?scp=80053540965&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.cell.2011.08.040
DO - https://doi.org/10.1016/j.cell.2011.08.040
M3 - مقالة
SN - 0092-8674
VL - 147
SP - 235
EP - 246
JO - Cell
JF - Cell
IS - 1
ER -