Loss of 5-HT2C Receptor Function Alters Motor Behavior and 5-HT2A Receptor Expression in Uninjured and Spinal Cord Injured Mice
Two subtypes of serotonin (5-HT) within the serotonin 2 class, the 5-HT2C receptor and the 5-HT2A receptor, are involved in the regulation of spinal motor function. The 5-HT2C receptor has been implicated in various aspects of volitional movement, such as locomotion, gait, coordination, and muscle contraction, as well as in involuntary motor behavior like spasms, which affect many individuals with spinal cord injury. Despite their known involvement in motor function, little is known about their physiological roles and the changes that occur 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-HT2C 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-HT2C 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-HT2C receptor and 5-HT2A receptor expression following spinal cord injury, western blot analysis was performed on lumbar and sacral spinal cord tissue from wildtype and 5-HT2C receptor knock-out mice before and after injury. Sex, genotype, and injury status significantly influenced 5-HT2C receptor and 5-HT2A 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-HT2C receptor plays a critical role in both volitional motor function and involuntary motor behavior. Additionally, we identified significant differences in the regional distribution and relative expression of the 5-HT2C receptor and 5-HT2A receptor based on sex, genotype, and injury status.