<title>Abstract</title>We recently found a significant association between exonic copy-number variations in the Rho GTPase activating protein 10 (<italic>Arhgap10</italic>) gene and schizophrenia in Japanese patients. Special attention was paid to one patient carrying a missense variant (p.S490P) in exon 17, which overlapped with an exonic deletion in the other allele. Accordingly, we generated a mouse model (<italic>Arhgap10</italic> S490P/NHEJ mice) carrying a missense variant and a coexisting frameshift mutation. We examined the spatiotemporal expression of <italic>Arhgap10</italic> mRNA in the brain and found the highest expression levels in the cerebellum, striatum, and nucleus accumbens (NAc), followed by the frontal cortex in adolescent mice. The expression levels of phosphorylated myosin phosphatase-targeting subunit 1 and phosphorylated p21-activated kinases in the striatum and NAc were significantly increased in <italic>Arhgap10</italic> S490P/NHEJ mice compared with wild-type littermates. <italic>Arhgap10</italic> S490P/NHEJ mice exhibited a significant increase in neuronal complexity and spine density in the striatum and NAc. There was no difference in touchscreen-based visual discrimination learning between <italic>Arhgap10</italic> S490P/NHEJ and wild-type mice, but a significant impairment of visual discrimination was evident in <italic>Arhgap10</italic> S490P/NHEJ mice but not wild-type mice when they were treated with methamphetamine. The number of c-Fos-positive cells was significantly increased after methamphetamine treatment in the dorsomedial striatum and NAc core of <italic>Arhgap10</italic> S490P/NHEJ mice. Taken together, these results suggested that schizophrenia-associated <italic>Arhgap10</italic> gene mutations result in morphological abnormality of neurons in the striatum and NAc, which may be associated with vulnerability of cognition to methamphetamine treatment.