Abstract
BackgroundIn 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.ResultsIn 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.ConclusionsThese 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.
Highlights
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
CNS muscarinic receptors play key roles in learning and memory, as well as in the regulation of many sensory, motor, and autonomic processes, while peripheral nervous system (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
Summary
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. 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 [3,4,5,6,7]. M4R is expressed abundantly in the striatum and is present at lower levels in several other brain regions including the cerebral cortex and hippocampus [11,15]
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