ASP2905, a specific inhibitor of the potassium channel Kv12.2 encoded by the Kcnh3 gene, is psychoactive in mice

Abstract

Schizophrenia is a major psychiatric disorder associated with positive and negative symptoms and cognitive impairments. In this study, we used animal models of behavior to evaluate the antipsychotic activity of ASP2905, a potent and selective inhibitor of the potassium channel Kv12.2 encoded by the Kcnh3/BEC1 gene. ASP2905 inhibited hyperlocomotion induced by methamphetamine and by phencyclidine. In contrast, ASP2905 did not affect spontaneous locomotion, suggesting that ASP2905 selectively inhibits abnormal behaviors induced by stimulants. Chronic infusion of ASP2905 significantly ameliorated phencyclidine-induced prolongation of immobility time in mice subjected to the forced swimming test. These findings suggest that ASP2905 potentially mitigates symptoms of schizophrenia, such as apathy. The antipsychotic clozapine also reversed phencyclidine-induced prolonged immobility, while risperidone and haloperidol had no effect. Assessment of the effects of ASP2905 on latent learning deficits in mice treated with phencyclidine as neonates subjected to the water-finding task showed that ASP2905 significantly ameliorated phencyclidine-induced prolongation of finding latency, which reflects latent learning performance. These findings suggest that ASP2905 potentially mitigates cognitive impairments caused by schizophrenia, such as attention deficits. In contrast, administration of clozapine did not ameliorate phencyclidine-induced prolongation of finding latency. Therefore, ASP2905 may alleviate the broad spectrum of symptoms of schizophrenia, including positive and negative symptoms and cognitive impairments, which is in contrast to currently available antipsychotics, which are generally only partially effective for ameliorating these symptoms.