CONVERGENT ROLE OF DENTATE GYRUS GRANULE CELLS IN TEMPORAL LOBE EPILEPSY AND AUTISM

Epilepsy and autism spectrum disorder (ASD) frequently co-occur, with approximately 12% of autistic individuals developing epilepsy. Deficits in social cognition—one of the core diagnostic feature of autism—are also commonly observed in patients with mesial temporal lobe epilepsy (mTLE). Converging evidence suggests that mTLE and ASD may share common mechanisms involving dysfunction of the hippocampal dentate gyrus (DG), however this hypothesis has never been sufficiently verified.
In human patients mutations in PTEN (negative regulator of PI3K–AKT–mTOR signaling) or 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 PTEN or Fmr1 gene selectively in adult DG granule cells is sufficient to evoke mTLE and social memory impairments. Animals with either PTEN-deficient or Fmr1-deficient DG granule cells developed chronic seizures reminiscent to those found in patients with mTLE. In addition, PTEN mutants demonstrated impaired interaction in bilateral social contact with conspecifics as well as strong hierarchy instability in cohort studies. While adequate social memory tests on Fmr1 mutants are pending, described results indicate that DG granule cells define a shared circuit mechanism for mTLE and ASD related social memory deficits.