Social Behavioral Deficits Coincide with the Onset of Seizure Susceptibility in Mice Lacking Serotonin Receptor 2c

The development of social behavior is strongly influenced by the serotonin system. Serotonin 2c receptor (5-HT(2c)R) is particularly interesting in this context considering that pharmacological modulation of 5-HT(2c)R activity alters social interaction in adult rodents. However, the role of 5-HT(2c)R in the development of social behavior is unexplored. Here we address this using Htr2c knockout mice, which lack 5-HT(2c)R. We found that these animals exhibit social behavior deficits as adults but not as juveniles. Moreover, we found that the age of onset of these deficits displays similar timing as the onset of susceptibility to spontaneous death and audiogenic-seizures, consistent with the hypothesis that imbalanced excitation and inhibition (E/I) may contribute to social behavioral deficits. Given that autism spectrum disorder (ASD) features social behavioral deficits and is often co-morbid with epilepsy, and given that 5-HT(2c)R physically interacts with Pten, we tested whether a second site mutation in the ASD risk gene Pten can modify these phenotypes. The age of spontaneous death is accelerated in mice double mutant for Pten and Htr2c relative to single mutants. We hypothesized that pharmacological antagonism of 5-HT(2c)R activity in adult animals, which does not cause seizures, might modify social behavioral deficits in Pten haploinsufficient mice. SB 242084, a 5-HT(2c)R selective antagonist, can reverse the social behavior deficits observed in Pten haploinsufficient mice. Together, these results elucidate a role of 5-HT(2c)R in the modulation of social behavior and seizure susceptibility in the context of normal development and Pten haploinsufficiency.