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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 by Tanaka, Rinako (author);Liao, Jingzhu (author);Hada, Kazuhiro (author);Mori, Daisuke (author);Nagai, Taku (author);Matsuzaki, Tetsuo (author);Nabeshima, Toshitaka (author);Kaibuchi, Kozo (author);Ozaki, Norio (author);Mizoguchi, Hiroyuki (author);Yamada, Kiyofumi (author) is a Medicine article available to read on EtoBox.

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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 in the Arhgap10 gene mimic the schizophrenia in a Japanese patient, exhibiting altered spine density, methamphetamine-induced cognitive dysfunction, and activation of RhoA/Rho-kinase signaling. However, it remains unclear whether the activation of RhoA/Rho-kinase signaling due to schizophrenia-associated Arhgap10 mutations causes the phenotypes of these model mice. Here, we investigated the effects of fasudil, a brain permeable Rho-kinase inhibitor, on altered spine density in the medial prefrontal cortex (mPFC) and on methamphetamine-induced cognitive impairment in a touchscreen‐based visual discrimination task in Arhgap10 S490P/NHEJ mice. Fasudil (20 mg/kg, intraperitoneal) suppressed the increased phosphorylation of myosin phosphatase–targeting subunit 1, a substrate of Rho-kinase, in the striatum and mPFC of Arhgap10 S490P/NHEJ mice. In addition, daily oral administration of fasudil (20 mg/kg/day) for 7 days ameliorated the reduced spine density of layer 2/3 pyramidal neurons in the mPFC.

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Author

Tanaka, Rinako (author);Liao, Jingzhu (author);Hada, Kazuhiro (author);Mori, Daisuke (author);Nagai, Taku (author);Matsuzaki, Tetsuo (author);Nabeshima, Toshitaka (author);Kaibuchi, Kozo (author);Ozaki, Norio (author);Mizoguchi, Hiroyuki (author);Yamada, Kiyofumi (author)

Publisher

Elsevier BV

Published

2023

Language

EN

Field

Medicine (Life Sciences)