窪田 悠力

1Abstract Copy number variations in theARHGAP10gene encoding Rho GTPase–activating protein 10 are significantly associated with schizophrenia. ARHGAP10 negatively regulates RhoA/Rho-kinase (ROCK) signaling. We previously demonstrated that fasudil, a non-selective ROCK inhibitor, exhibited antipsychotic-like effects in several mouse models of schizophrenia. ROCK has two subtypes, ROCK1 and ROCK2. ROCK1 is mainly expressed in the thymus and blood, while ROCK2 is predominantly expressed in the brain. Therefore, it is expected that like fasudil, selective ROCK2 inhibitors will exhibit antipsychotic-like effects, accompanied by a lower incidence of adverse effects due to ROCK1 inhibition. Here, we used genetic and pharmacological models of schizophrenia to investigate whether the selective ROCK2 inhibitor KD025 would show antipsychotic-like effects with a favorable adverse effect profile. Oral administration of KD025 suppressed the abnormal increase in the phosphorylation level of myosin phosphatase–targeting subunit 1, a substrate of ROCK, and ameliorated the decreased spine density of layer 2/3 pyramidal neurons in the medial prefrontal cortex ofArhgap10S490P/NHEJ mice. Furthermore, KD025 mitigated the methamphetamine-induced impairment of visual discrimination (VD) inArhgap10S490P/NHEJ and wild-type mice. KD025 also reduced MK-801–induced impairments of VD, novel object recognition, and hyperlocomotion. Regarding side effects that are commonly seen with typical antipsychotics, KD025 did not affect systolic blood pressure and did not induce extrapyramidal symptoms, hyperprolactinemia, or hyperglycemia at the effective dosage in naïve wild-type mice. Taken together, KD025 shows antipsychotic-like effects with a favorable adverse effect profile in genetic and pharmacological mouse models of schizophrenia.

Schizophrenia is a psychiatric disorder characterized by positive, negative, and cognitive symptoms. MK-801, an N-methyl-D-aspartate receptor antagonist, has been used to induce schizophrenia-like behaviors in animal models. Here, we employed IntelliCage, an automated system used for tracking behavior, to assess schizophrenia-like behaviors in MK-801-treated mice under semi-naturalistic conditions. Mice that had been treated with MK-801 for 2 weeks were analyzed for locomotion, emotional, and cognitive functions. Repeated MK-801-treated mice exhibited transient hyperactivity in a novel environment, without significant changes in overall circadian activity. Sucrose preference remained intact, suggesting preserved reward sensitivity. However, less time spent in the corner during the early phase of the competition test indicated reduced competitive behavior for limited water rewards. In the behavioral flexibility test, repeated MK-801-treated mice showed impaired reversal learning, suggesting reduced cognitive flexibility, although the acquisition of initial place discrimination was comparable to that observed in control mice. These behavioral impairments parallel core symptoms of schizophrenia, particularly in the social and cognitive domains. Our findings demonstrate the utility of IntelliCage in detecting behavioral phenotypes over prolonged periods in group-housed settings. This study provides an ecologically valid platform for assessing schizophrenia-like behaviors and may facilitate the development of translationally relevant therapeutic interventions.

Background and Purpose Alterations in tryptophan‐kynurenine (TRP‐KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic–pituitary–adrenal (HPA) axis. We have shown that deficiency of kynurenine 3‐monooxygenase (KMO) induces depression‐like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP‐KYN pathway in stress‐induced behavioural changes and the regulation of the HPA axis. Experimental Approach Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP‐KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS‐induced behavioural changes and an increase in serum corticosterone (CORT) concentration. Key Results CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. Kmo^+/− mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short‐term CUMS. Nicotine attenuated CUMS‐induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin‐releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine. Conclusions and Implications CUMS‐induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.