Abstracts

Rationale: There is increasing evidence of a strong comorbidity between autism and epilepsy. Recent studies have shown that genetic deletion of genes that modulate the mTOR signaling pathway result in an autistic phenotype. These genes have also been demonstrated to play a critical role in cortical dysplasia and tuberous sclerosis complex. Furthermore, hypereractivation of the mTOR pathway has been reported in several animal models of epilepsy. However, there has been less emphasis on behavioral consequences due to hyperactivation of mTOR signaling. Here, we evaluated the behavioral consequences of mTOR hyperactivation by using neuron subset-specific (NS-Pten) conditional knockout mice. Methods: Multiple cohorts of NS-Pten knockouts and wildtype mice were examined through a battery of behavioral tests. We first examined isolation-induced ultrasonic vocalizations in postnatal day 9 and 10 pups. We examined their locomotion and anxiety in an open field test. We examined their learning and memory through a standard fear conditioning test and a separate cohort was examined in a trace-fear conditioning test. We examined their social behavior in a three chamber test and a social partition test. We examined their repetitive behavior in a marble burying test. Results: The NS-Pten KO mice displayed hyperactivity in the open field test compared to controls, p < 0.001; and spent significantly less time in the center of the open field, p < 0.05. They showed deficits in social behavior by interacting less with a mouse in the social chamber test, p < 0.05; and spent less time at a partition with a novel mouse in the social partition test, p < 0.05. The NS-Pten knockout pups did not show a change in the number or duration of ultrasonic vocalizations when removed from their mother. The NS-Pten mice demonstrate alterations in repetitive behavior, as measured in the marble burying test. In addition to deficits in the behavioral features that describe autism, they have learning and memory deficits in contextual learning in the conditioned fear test, but did not show a difference in their freezing to a tone (conditioned stimulus) compared to wildtype mice. Conclusions: These findings demonstrate that hyperactivation due to genetic deletion of Pten results in long-term alterations in social behavior, anxiety, repetitive behavior, and learning and memory. It has previously been demonstrated that NS-Pten mice develop seizures at 4 weeks of age that increase in duration as they age. Additionally, inhibition of mTOR prevents the progression of epilepsy in NS-PTEN mice. Our data demonstrates that NS-Pten mice are a valuable tool to examine the behavioral consequences due to mTOR hyperactivation. Future studies could examine whether the behavioral deficits are reversed with mTOR inhibitors. In addition, future studies could correlate the epileptogenic changes that occur in the NS-Pten mice along with the behavioral changes.