Loss of 5-HT _2C Receptor Function Alters Motor Behavior in Male and Female Mice With and Without Spinal Cord Injury

The 5-HT _2C receptor is involved in the regulation of spinal motor function, specifically in both volitional and involuntary motor behavior. It contributes to various aspects of voluntary movement, such as locomotion, gait, coordination, and muscle contraction, as well as to involuntary motor behavior like spasms, which affect many individuals with spinal cord injury. Despite its known involvement in motor function, little is known about the physiological role of the 5-HT _2C receptor and the changes it undergoes after spinal cord injury. In this study, we have investigated the volitional and involuntary motor behavior of male and female uninjured and spinal cord injured knock-out mice that lack the functional 5-HT _2C receptor by comparing these genetically manipulated mice to typical-functioning sex-matched wildtype mice. Behavioral assessments revealed differences in volitional muscle strength and coordination, as well as hyperreflexia, between the groups observed. Additionally, ex vivo sacral cord preparation data suggest that 5-HT _2C receptor knock-out mice exhibit less spasm-like activity than wildtype mice, corroborating our results from behavioral testing in which the flexor withdrawal reflex of the hindlimbs was assessed. To investigate potential compensatory changes in 5-HT _2C receptor expression following spinal cord injury, western blot analysis was performed on lumbar and sacral spinal cord tissue from wildtype and 5-HT _2C receptor knock-out mice before and after injury. Both sex and injury status significantly influenced 5-HT _2C receptor relative expression and distribution of these receptors in both spinal cord regions. Through a comprehensive approach combining behavioral assessments, electrophysiological experiments, and whole-tissue protein analysis, our findings provide strong evidence that the 5-HT _2C receptor plays a critical role in both volitional motor function and involuntary motor behavior, and the relative expression of the 5-HT _2C receptor is influenced by both sex and injury status.