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Dysfunction of postsynaptic proteins is strongly linked to neurodevelopmental and psychiatric disorders. SAP90\/PSD95-associated protein 4 (SAPAP4; also known as DLGAP4) is a key component of the PSD95\u2013SAPAP\u2013SHANK excitatory postsynaptic scaffolding complex, which plays important roles at synapses. However, the exact function of the SAPAP4 protein in the brain is poorly understood. Here, we report that Sapap4 knockout (KO) mice have reduced spine density in the prefrontal cortex and abnormal compositions of key postsynaptic proteins in the postsynaptic density (PSD) including reduced PSD95, GluR1, and GluR2 as well as increased SHANK3. These synaptic defects are accompanied by a cluster of abnormal behaviors including hyperactivity, impulsivity, reduced despair\/depression-like behavior, hypersensitivity to low dose of amphetamine, memory deficits, and decreased prepulse inhibition, which are reminiscent of mania. Furthermore, the hyperactivity of Sapap4 KO mice could be partially rescued by valproate, a mood stabilizer used for mania treatment in humans. Together, our findings provide evidence that SAPAP4 plays an important role at synapses and reinforce the view that dysfunction of the postsynaptic scaffolding protein SAPAP4 may contribute to the pathogenesis of hyperkinetic neuropsychiatric disorder.<\/jats:p>","DOI":"10.1093\/cercor\/bhac123","type":"journal-article","created":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T12:08:28Z","timestamp":1646482108000},"page":"1104-1118","source":"Crossref","is-referenced-by-count":5,"title":["<i>Sapap4<\/i>deficiency leads to postsynaptic defects and abnormal behaviors relevant to hyperkinetic neuropsychiatric disorder in mice"],"prefix":"10.1093","volume":"33","author":[{"given":"Tianhua","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Brain Functional Genomics (STCSM & MOE) , School of Psychology and Cognitive Science, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062 , 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Institute of Brain and Cognitive Science at NYU Shanghai , 3663 North Zhongshan Road, Shanghai, 200062 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoping","family":"Feng","sequence":"additional","affiliation":[{"name":"McGovern Institute for Brain Research , Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge, Massachusetts, 02139 , USA"},{"name":"Stanley Center for Psychiatric Research , Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts, 02142 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunxia","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Brain Functional Genomics (STCSM & MOE) , School of Psychology and Cognitive Science, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062 , 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