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Human genome studies have revealed that the IQSEC2 gene is associated with X-linked neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism. In this study, we examined the behavior and synapse function in IQSEC2 knockout (KO) mice that we generated using CRIPSR\/Cas9-mediated genome editing to solve the relevance between IQSEC2 deficiency and the pathophysiology of neurodevelopmental disorders. IQSEC2 KO mice exhibited autistic behaviors, such as overgrooming and social deficits. We identified that up-regulation of c-Fos expression in the medial prefrontal cortex (mPFC) induced by social stimulation was significantly attenuated in IQSEC2 KO mice. Whole cell electrophysiological recording identified that synaptic transmissions mediated by \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), N-methyl-D-aspartate receptor (NMDAR), and \u03b3-aminobutyric acid receptor (GABAR) were significantly decreased in pyramidal neurons in layer 5 of the mPFC in IQSEC2 KO mice. Reexpression of IQSEC2 isoform 1 in the mPFC of IQSEC2 KO mice using adeno-associated virus (AAV) rescued both synaptic and social deficits, suggesting that impaired synaptic function in the mPFC is responsible for social deficits in IQSEC2 KO mice.<\/jats:p>","DOI":"10.3390\/cells10102724","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T04:51:57Z","timestamp":1634100717000},"page":"2724","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3385-4075","authenticated-orcid":false,"given":"Anuradha","family":"Mehta","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3263-4986","authenticated-orcid":false,"given":"Yoshinori","family":"Shirai","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emi","family":"Kouyama-Suzuki","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Yoshizawa","sequence":"additional","affiliation":[{"name":"Research Center for Advanced Science and Technology, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0868-2563","authenticated-orcid":false,"given":"Toru","family":"Yanagawa","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4195-2804","authenticated-orcid":false,"given":"Takuma","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"},{"name":"Department of NeuroHealth Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1673-4637","authenticated-orcid":false,"given":"Katsuhiko","family":"Tabuchi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan"},{"name":"Department of NeuroHealth Innovation, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.neures.2007.10.013","article-title":"IQ-ArfGEF\/BRAG1 is a guanine nucleotide exchange factor for Arf6 that interacts with PSD-95 at postsynaptic density of excitatory synapses","volume":"60","author":"Sanda","year":"2008","journal-title":"Neurosci. 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