Inhibition of Rho-kinase ameliorates decreased spine density in the medial prefrontal cortex and methamphetamine-induced cognitive dysfunction in mice carrying schizophrenia-associated mutations of the Arhgap10 gene

• DOI: 10.1016/j.phrs.2022.106589
• Publication Date: 2022-11-30T16:24:47Z
• Authors: Rinako Tanaka; Jingzhu Liao; Kazuhiro Hada; Daisuke Mori; Taku Nagai; Tetsuo Matsuzaki; Toshitaka Nabeshima; Kozo Kaibuchi; Norio Ozaki; Hiroyuki Mizoguchi; Kiyofumi Yamada
• Keywords: Methamphetamine

Copy-number variations in the ARHGAP10 gene encoding Rho GTPase-activating protein 10 are associated with schizophrenia. Model mice (Arhgap10 S490P/NHEJ mice) that carry "double-hit" mutations Arhgap10 mimic schizophrenia a Japanese patient, exhibiting altered spine density, methamphetamine-induced cognitive dysfunction, and activation of RhoA/Rho-kinase signaling. However, it remains unclear whether signaling due to schizophrenia-associated causes phenotypes these model mice. Here, we investigated effects fasudil, brain permeable Rho-kinase inhibitor, on density medial prefrontal cortex (mPFC) impairment touchscreen‑based visual discrimination task Fasudil (20 mg/kg, intraperitoneal) suppressed increased phosphorylation myosin phosphatase-targeting subunit 1, substrate Rho-kinase, striatum mPFC In addition, daily oral administration fasudil mg/kg/day) for 7 days ameliorated reduced layer 2/3 pyramidal neurons mPFC. Moreover, (3-20 rescued methamphetamine (0.3 mg/kg)-induced Our results suggest plays significant roles neuropathological changes morphology vulnerability cognition mutations.