ARHGAP10 is a member of the RhoGAP superfamily, and involved in RhoA/ROCK signaling. Recently, our group has identified ARHGAP10 gene mutation in Japanese schizophrenia patients by genome-wide CNV analysis. We also found that a ROCK inhibitor Y-27632 restored the impairment of neurite elongation of TH-positive neurons that had been differentiated from the patient-derived iPS cells. In this research, to clarify a potential role of RhoA/ROCK signal as a new therapeutic target for schizophrenia, we examined the effect of fasudil, a ROCK inhibitor, on MK-801induced behavioral impairment and neurotransmitter release in nucleus accumbens (NAc) in C57BL/6j male mice. We performed locomotor activity test, novel object recognition test (NORT), social interaction test (SI), and prepulse inhibition test (PPI). Fasudil (10-20 mg/kg) was intraperitoneally administered 5 min before the behavioral tests. We also measured the extracellular dopamine and serotonin levels in the NAc using an in vivo microdialysis method. Fasudil (10 or 20 mg/kg) restored MK-801-induced hyperlocomotion and the impairment of performance in the NORT, SI and PPI tests. Fasudil (20 μM) suppressed the depolarization-evoked dopamine and serotonin releases in the NAc, while it increased the basal serotonin levels. These observations suggest that the RhoA/ROCK signal has potential as a therapeutic target for schizophrenia and fasudil has some antipsychotic-like effects in a preclinical animal model of schizophrenia.

No abstract