M4 muscarinic receptor knockout mice display abnormal social behavior and decreased prepulse inhibition

Abstract

Background: In the central nervous system (CNS), the muscarinic system plays key roles in learning and memory, as well as in the regulation of many sensory, motor, and autonomic processes, and is thought to be involved in the pathophysiology of several major diseases of the CNS, such as Alzheimer's disease, depression, and schizophrenia. Previous studies reveal that M₄ muscarinic receptor knockout (M₄R KO) mice displayed an increase in basal locomotor activity, an increase in sensitivity to the prepulse inhibition (PPI)-disrupting effect of psychotomimetics, and normal basal PPI. However, other behaviorally significant roles of M₄R remain unclear. Results: In this study, to further investigate precise functional roles of M₄R in the CNS, M₄R KO mice were subjected to a battery of behavioral tests. M₄R KO mice showed no significant impairments in nociception, neuromuscular strength, or motor coordination/learning. In open field, light/dark transition, and social interaction tests, consistent with previous studies, M₄R KO mice displayed enhanced locomotor activity compared to their wild-type littermates. In the open field test, M₄R KO mice exhibited novelty-induced locomotor hyperactivity. In the social interaction test, contacts between pairs of M₄R KO mice lasted shorter than those of wild-type mice. In the sensorimotor gating test, M₄R KO mice showed a decrease in PPI, whereas in the startle response test, in contrast to a previous study, M₄R KO mice demonstrated normal startle response. M₄R KO mice also displayed normal performance in the Morris water maze test. Conclusions: These findings indicate that M₄R is involved in regulation of locomotor activity, social behavior, and sensorimotor gating in mice. Together with decreased PPI, abnormal social behavior, which was newly identified in the present study, may represent a behavioral abnormality related to psychiatric disorders including schizophrenia.