DENTATE GYRUS GRANULE CELLS DEFINE A SHARED CIRCUIT MECHANISM FOR EPILEPSY AND AUTISM

Epilepsy and autism spectrum disorder (ASD) frequently co-occur, with approximately 20% of autistic individuals developing epilepsy. ASD-related cognitive alterations are also commonly observed in patients with mesial temporal lobe epilepsy (mTLE). Converging evidence suggests that mTLE and ASD may share common dysfunction of the hippocampal pattern separation mediated by dentate gyrus (DG) granule cells however, this hypothesis has never been sufficiently verified. In human patients, mutations in the PTEN (negative regulator of PI3K–AKT–mTOR signaling) or the FMR1 gene (Fragile X Messenger Ribonucleoprotein 1) are critically attributed to ASD. In this study, using mouse models and viral gene transfer, we examined whether downregulation of either the PTEN or the Fmr1 gene selectively in adult DG granule cells is sufficient to evoke mTLE and pattern separation impairments. Animals with either PTEN-deficient or Fmr1-deficient DG granule cells developed chronic seizures reminiscent of those found in patients with mTLE. In addition, PTEN and FMR1 mutants demonstrate impaired behavioral pattern separation, which in the case of PTEN mutants was also confirmed with extracellular recordings. While adequate electrophysiological tests on FFMR1 mutants are pending, the described results, supported by mathematical models, indicate that DG granule cells may play a convergent role in common ASD and mTLE pathophysiology.