Inhibition of reactive oxygen species production accompanying alternatively activated microglia by risperidone in a mouse ketamine model of schizophrenia

Author:

Fujikawa Risako1,Yamada Jun1,Maeda Shoichiro1,Iinuma Kyoko M.1,Moriyama Genki2,Jinno Shozo1ORCID

Affiliation:

1. Department of Anatomy and Neuroscience, Graduate School of Medical Sciences Kyushu University Fukuoka Japan

2. Kawasaki Medical School Kurashiki Japan

Abstract

AbstractRecent studies have highlighted the potential involvement of reactive oxygen species (ROS) and microglia, a major source of ROS, in the pathophysiology of schizophrenia. In our study, we explored how the second‐generation antipsychotic risperidone (RIS) affects ROS regulation and microglial activation in the hippocampus using a mouse ketamine (KET) model of schizophrenia. KET administration resulted in schizophrenia‐like behaviors in male C57BL/6J mice, such as impaired prepulse inhibition (PPI) of the acoustic startle response and hyper‐locomotion. These behaviors were mitigated by RIS. We found that the gene expression level of an enzyme responsible for ROS production (Nox2), which is primarily associated with activated microglia, was lower in KET/RIS‐treated mice than in KET‐treated mice. Conversely, the levels of antioxidant enzymes (Ho‐1 and Gclc) were higher in KET/RIS‐treated mice. The microglial density in the hippocampus was increased in KET‐treated mice, which was counteracted by RIS. Hierarchical cluster analysis revealed three morphological subtypes of microglia. In control mice, most microglia were resting‐ramified (type I, 89.7%). KET administration shifted the microglial composition to moderately ramified (type II, 44.4%) and hyper‐ramified (type III, 25.0%). In KET/RIS‐treated mice, type II decreased to 32.0%, while type III increased to 34.0%. An in vitro ROS assay showed that KET increased ROS production in dissociated hippocampal microglia, and this effect was mitigated by RIS. Furthermore, we discovered that a NOX2 inhibitor could counteract KET‐induced behavioral deficits. These findings suggest that pharmacological inhibition of ROS production by RIS may play a crucial role in ameliorating schizophrenia‐related symptoms. Moreover, modulating microglial activation to regulate ROS production has emerged as a novel avenue for developing innovative treatments for schizophrenia. image

Funder

Japan Society for the Promotion of Science

Publisher

Wiley

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