PTEN LOSS IN MATURE DENTATE GYRUS GRANULE CELLS DISRUPTS CIRCUIT COMPUTATION AN DRIVES EPILEPSY THROUGH COMPARTMENTALIZED DYSREGULATION OF MTOR/ERK SIGNALING

Loss of the tumor suppressor PTEN in dentate gyrus granule cells (GCs) is strongly associated with epilepsy, cognitive impairment, and autism-related phenotypes, yet the cellular mechanisms linking PTEN loss to network-level dysfunction remain incompletely understood. Using an adult, GC-restricted conditional PTEN knockout (PTEN-cKO) model, we show that PTEN loss induces a multifaceted phenotype characterized by neuronal hypertrophy, mossy fiber pathway remodeling, and a progressive decline in intrinsic excitability despite preserved neuronal viability. At the circuit level, multi-electrode array recordings demonstrate impaired single-cell pattern separation following perforant path stimulation, accompanied by deficits in behavioral pattern separation and reduced recruitment of dentate and CA3 neuronal ensembles assessed by c-Fos mapping. These functional impairments emerge alongside spontaneous epileptiform activity and recurrent seizures confirmed by video-EEG, as well as hippocampal sclerosis-like pathology including astrogliosis, microgliosis, leukocyte infiltration, and selective hilar–CA3 vulnerability. Molecular analyses reveal widespread engagement of translational signaling, with robust rpS6 phosphorylation extending to neighboring non-recombined cells, while new immunohistochemical evidence demonstrates striking compartmentalization of upstream pathways, with mTORC1 activation predominating in dendritic domains and phospho-ERK1/2 selectively enriched in mossy fiber axons. Preliminary observations from a parallel fmr1-cKO model, in which both mTOR and ERK dysregulation are implicated, support the plausibility of convergent mechanisms in hippocampal circuit dysfunction. Ongoing analyses of spontaneous and miniature excitatory synaptic transmission aim to further resolve synaptic contributions to this functionally compromised state. Together, these findings position PTEN loss as a driver of persistent maladaptive neuronal dysfunction linking mTOR/ERK signaling dysregulation with circuit computation failure and epileptogenesis.