A Two-Hit Approach Inducing Flurothyl Seizures in Fmr1 Knockout Mice Impacts Anxiety and Repetitive Behaviors

Abstract

Background: Fragile X Syndrome (FXS) is the leading monogenetic cause of autism spectrum disorder (ASD) and is associated with seizures. We examined the impact of repeated seizures on the behavioral and molecular changes in male Fmr1 knockout (KO) mice and wild-type (WT) mice. Methods: Seizures were induced by administering three flurothyl seizures per day across postnatal days (PD) 7–11, for a total of 15 seizures. In adulthood, mice were tested in a battery of behavioral tasks to assess long-term behavioral deficits. Results: The two-hit impact of a Fmr1 knockout and seizures resulted in decreased anxiety-like behavior in the elevated plus maze test and a longer latency to their first nose poke (repetitive behavior). Seizures resulted in decreased activity, decreased repetitive behavior (grooming and rearings), and decreased social behavior, while they also increased habituation to auditory stimuli and increased freezing in delayed fear conditioning in both KO and control mice. KO mice displayed increased repetitive behavior in the open field task (clockwise revolutions) and repeated nose pokes, and decreased anxiety in the open field test. No differences in mTOR signaling were found. Conclusions: These findings further illuminate the long-term effects of synergistic impact of two hits on the developing brain.

Keywords

• epilepsy
• mTOR
• early life seizures
• two-hit
• double-hit
• developmental epilepsy