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

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.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.Members of the muscarinic acetylcholine receptor family (M1-M5R) are widely expressed in the central nervous system (CNS) and the peripheral nervous system (PNS) [1,2]. CNS muscarinic receptors play key roles in learning and memory, as well as in the regulation of many sensory, motor, and autonomic processes, while PNS muscarinic receptors mediate the activity of acetylcholine released from parasympathetic nerves [3]. Reduced or increased signaling through distinct muscarinic acetylcholine receptor subtypes is implicated in the pathophysiology of several major diseases of the CNS, including Alzheimer's and Parkinson's diseases, depression, epilepsy, and schizophrenia [3-7].Based on the overlapping expression patterns of the different