Rationale: Alterations in central serotonergic signaling may play a crucial role in epilepsy’s psychiatric comorbidities and the propensity for seizure-induced cardiorespiratory arrest. Our lab previously reported that transgenic mice with a deletion of the X-linked serotonin-2C receptor (loxTB Htr2c) display spontaneous seizures in both male and female mice beginning at two months of age, together with premature mortality seen predominantly in males. To explore how 5-HT2C receptor signaling may impact aspects of emotional behavior and overall wellbeing, we undertook an extensive behavioral characterization of this mouse model. Methods: Eight to ten week old sex-matched wild-type and hemizygous mutant loxTB 5Htr2c littermates were assessed in an open field arena (45x45x45 cm) for one hour, with live center-point tracking conducted via Ethovision XT 14. To obtain prolonged undisturbed recordings of spontaneous behavior across the day-night cycle, wild-type and mutant male mice were also examined within Noldus Phenotyper home-cages (30x30x47cm). Live aerial videotracking was employed to quantify mouse position and horizontal displacement, and cages were instrumented to measure drinking (lickometers), feeding (beam-metered food hoppers), wheel running and sheltering behavior. Following baseline recordings, a series of provocative maneuvers were utilized to assess measures of risk aversion, exercise motivation, sociability and seizure threshold. Results: In open field testing, male Htr2c-/Y mice (n=10) traversed greater distances than wildtype (n=9) littermates. In contrast, no differences in open field behavior were observed across wildtype, heterozygous or homozygous mutant female mice. In instrumented home-cages, male Htr2c-/Y mutant mice displayed striking nocturnal hyperactivity and relatively reduced feeding times without changes in sheltering or noninvasively defined “sleep”. Male mutant mice also displayed a more pronounced immobility response to a nocturnal light spot or a cage swap provocation compared to wildtype littermates. When provided access to a running wheel, Htr2c-/Y mice displayed significantly elevated wheel running rates. No obvious changes in sociability were observed during a 2-hour long encounter within the home-cage with an age and sex-matched novel mouse. Finally, following an injection of a subconvulsant dose pentylenetetrazole (30mg/kg), Htr2c-/Y mice displayed a greater incidence of tonic-clonic convulsions and overall mortality. Conclusions: These results reveal that deficits in the X-linked 5-HT2C receptor function that enhance seizure risk also modulate changes in spontaneous and stress-evoked psychomotor behavior in male 5-HT2C mutant mice. In ongoing studies, we continue to explore the mechanisms underlying the sexual dimorphism observed across these pleiotropic correlates of ictal and interictal activity in 5-HT2C receptor mutant mice. Funding: Please list any funding that was received in support of this abstract.: This work was funded by NINDS U01 NS090340 (JLN) and F32 NS105329 (CAM) and seed funds from the Office of Research at Baylor College of Medicine (VK).
