Lasting social deficits mediated by recurrent pentylenetetrazole-induced seizures in mice
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Autism is a neurodevelopmental disorder characterized by core impairments in social reciprocity and communication, together with a repetitive/restricted pattern of behavioral interests. Up to a third of individuals with autism also suffer from epilepsy, and human cross-sectional studies have demonstrated that the co-existence of epileptic seizures tends to result in more severe autistic phenotypes. It remains unknown as to whether this phenomenon is a result of anticonvulsant medications, the underlying autism promoting insult or the effect of recurrent seizures themselves. In an attempt to establish a connection between recurrent seizures and their impact on social behavior, we designed a simple and reliable mouse model of recurrent seizures by employing daily intraperitoneal injections of the chemoconvulsant PTZ (pentylenetetrazole, a GABA antagonist). Social motivation was assayed on the three-chamber social interaction test. We observed that 24 hours following 10 daily injections of a subconvulsant dose of PTZ (30mg/kg), both male and female mice display a reduction in social interaction. Mice exposed to seizures also vocalized significantly less than control mice. These social impairments were not related to a gross impairment in locomotion, olfaction, or exploration and were found to persist up to 30 days following their last seizure. These results suggest that recurrent seizures themselves may be facilitating some of the heightened social deficits frequently seen with autism and epilepsy. These results also lend naturally to i) studies examining molecular and structural neuroplastic changes occurring in brain circuits that are important for social behavior, and ii) data that may highlight the contributions of specific genes that may accelerate or protect against the development of seizure-induced impairments in social behavior.