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Award type：Award from international society, conference, symposium, etc.  Country：Singapore

Award type：Award from international society, conference, symposium, etc.  Country：Singapore

Award type：Award from international society, conference, symposium, etc.  Country：Korea, Republic of

Authorship：Lead author   Language：English  

DOI： 10.1101/2024.09.16.613372

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Molecular Sciences  

Schizophrenia is one of the most serious psychiatric disorders and is characterized by reductions in both brain volume and spine density in the frontal cortex. RhoA belongs to the RAS homolog (Rho) family and plays critical roles in neuronal development and structural plasticity via Rho-kinase. RhoA activity is regulated by GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). Several variants in GAPs and GEFs associated with RhoA have been reported to be significantly associated with schizophrenia. Moreover, several mouse models carrying schizophrenia-associated gene variants involved in RhoA/Rho-kinase signaling have been developed. In this review, we summarize clinical evidence showing that variants in genes regulating RhoA activity are associated with schizophrenia. In the last half of the review, we discuss preclinical evidence indicating that RhoA/Rho-kinase is a potential therapeutic target of schizophrenia. In particular, Rho-kinase inhibitors exhibit anti-psychotic-like effects not only in Arhgap10 S490P/NHEJ mice, but also in pharmacologic models of schizophrenia (methamphetamine- and MK-801-treated mice). Accordingly, we propose that Rho-kinase inhibitors may have antipsychotic effects and reduce cognitive deficits in schizophrenia despite the presence or absence of genetic variants in small GTPase signaling pathways.

DOI： 10.3390/ijms242115623

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Pharmacological Research  

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. Moreover, fasudil (3–20 mg/kg, intraperitoneal) rescued the methamphetamine (0.3 mg/kg)-induced cognitive impairment of visual discrimination in Arhgap10 S490P/NHEJ mice. Our results suggest that Rho-kinase plays significant roles in the neuropathological changes in spine morphology and in the vulnerability of cognition to methamphetamine in mice with schizophrenia-associated Arhgap10 mutations.

DOI： 10.1016/j.phrs.2022.106589

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ejphar.2022.175207

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：Wiley  

DOI： 10.1111/bph.16112

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Language：Japanese   Publisher：Japanese Pharmacological Society  

Copy number variants in the<i> ARHGAP10</i> gene are associated with schizophrenia (SCZ). We have previously demonstrated that Rho-kinase (ROCK) inhibitor, fasudil, ameliorates the decreased spine density in the medial prefrontal cortex (mPFC) of <i>Arhgap10 </i>S490P/NHEJ<i> </i>mice carrying the variants that mimic the <i>ARHGAP10</i> variants found in a Japanese SCZ patient. Accordingly, we have proposed that ROCK is a potentially novel therapeutic target in SCZ. It is well known that there are two subtypes of ROCK, ROCK1 and ROCK2, and that fasudil inhibits both subtypes. Since ROCK2 is highly expressed in the brain, here we evaluated the effect of a selective ROCK2 inhibitor, belumosudil (KD025), on spine density in <i>Arhgap10 S490P/NHEJ </i>mice. We measured the spine density of pyramidal neurons in layer 2/3 of the mPFC in <i>Arhgap10 </i>S490P/NHEJ<i> </i>mice following daily oral administration of KD025 for one week. Moreover, we evaluated the general behaviors in an open field and systolic blood pressure after KD025 treatment. KD025 ameliorated decreased spine density of cortical neurons in the mPFC of <i>Arhgap10 </i>S490P/NHEJ<i> </i>mice, but had little effects on general behaviors and systolic blood pressure induced by fasudil. These observations suggest that ROCK2 is a more appropriate therapeutic target in SCZ, with little inducibility of hypotension.

DOI： 10.1254/jpssuppl.97.0_1-b-yia2-5

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Authorship：Lead author   Language：English   Publishing type：Research paper, summary (national, other academic conference)  

DOI： https://doi.org/10.1254/jpssuppl.95.0_2-p-168

Authorship：Lead author   Language：English   Publishing type：Research paper, summary (national, other academic conference)  

DOI： https://doi.org/10.1254/jpssuppl.94.0_1-y-f3-4

Event date： 2024.5

Language：English   Presentation type：Oral presentation (general)  

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Event date： 2023.12

Language：English  

Event date： 2023.9

Language：Japanese   Presentation type：Poster presentation  

Event date： 2023.7

Language：English  

Country：United Kingdom  

Event date： 2021.10

Language：English   Presentation type：Poster presentation  

Country：Singapore