Mice carrying a schizophrenia-associated mutation of the Arhgap10 gene are vulnerable to the effects of methamphetamine treatment on cognitive function: association with morphological abnormalities in striatal neurons

Kazuhiro Hada,Norimichi Itoh,Akira Sobue,Toshitaka Nabeshima,Daisuke Mori,Norio Ozaki,Itaru Kushima,Masahito Sawahata,Hiroyuki Mizoguchi,Kiyofumi Yamada,Bolati Wulaer,Taku Nagai

doi:10.1186/s13041-021-00735-4

Kazuhiro Hada, Norimichi Itoh + Show 10 more

Open Access

https://doi.org/10.1186/s13041-021-00735-4

Copy DOI

Abstract

We recently found a significant association between exonic copy-number variations in the Rho GTPase activating protein 10 (Arhgap10) 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 (Arhgap10 S490P/NHEJ mice) carrying a missense variant and a coexisting frameshift mutation. We examined the spatiotemporal expression of Arhgap10 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 Arhgap10 S490P/NHEJ mice compared with wild-type littermates. Arhgap10 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 Arhgap10 S490P/NHEJ and wild-type mice, but a significant impairment of visual discrimination was evident in Arhgap10 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 Arhgap10 S490P/NHEJ mice. Taken together, these results suggested that schizophrenia-associated Arhgap10 gene mutations result in morphological abnormality of neurons in the striatum and NAc, which may be associated with vulnerability of cognition to methamphetamine treatment.

Highlights

Schizophrenia is a highly debilitating mental disorder that affects about 1% of the overall population
The phospho-PAK1/2 (Ser144/141) levels were higher in the striatum and nucleus accumbens (NAc) of Arhgap10 S490P/non-homologous end-joining (NHEJ) mice than those in wild-type littermates (Fig. 2d–f ). These results suggested that Arhgap10 S490P/NHEJ mice have an abnormality in the Rho signaling pathway in the striatum and NAc
All data are expressed as means ± SEM (n = 8–15 neurons from 4–5 mice in each genotype) in the striatum and NAc of Arhgap10 S490P/NHEJ mice may be detected by the task

Summary

Introduction

Schizophrenia is a highly debilitating mental disorder that affects about 1% of the overall population. Genomic studies have suggested a role for rare copy-number variations (CNVs), defined as copy number changes including deletions and duplications of genomic regions in schizophrenia. Rare CNVs in specific loci have been identified as risk factors for schizophrenia, including deletions at 1q21.1, NRXN1, 3q29, 15q11.2, 15q13.3, and 22q11.2 and duplications at 1q21.1, 7q11.23, 15q11.2-q13.1, 16p13.1, and 16p11.2 [7–12]. We recently found a significant association between schizophrenia and exonic CNVs in the Rho GTPase activating protein 10 (Arhgap10) gene [13]. One schizophrenia patient (Case #5) had a missense variant (p.S490P) in exon 17, which overlapped with an exonic deletion on the other allele and was located in the RhoGAP domain, leading to the activation of RhoA signaling [13]. Two mutations in the same gene, such as in Case #5, have been proposed to represent a relevant genetic model of severe schizophrenia [16]. The model mice, Arhgap S490P/NHEJ, carrying a missense variant (p.S490P) and a coexisting frameshift mutation caused by non-homologous end-joining (NHEJ) showed an increase in anxiety-related behavior in the elevated plus-maze test and a hypersensitivity to methamphetamine in the locomotor test [13]

Methods

Results

Conclusion