T Cell-Mediated Targeting of Interneurons in Mice Shapes Hippocampal Remodeling and Epilepsy.

OBJECTIVE: Autoimmune encephalitis (AE) is associated with autoantibodies targeting distinct neuronal populations. In AE, antibodies against glutamate decarboxylase 65 (GAD65), expressed in GABAergic interneurons, are frequently detected. In GAD65-AE, hippocampal biopsies often show infiltrates of CD8+ cytotoxic T cells (CTLs), suggesting a prominent T cell-associated pathology. This has led to the hypothesis that CTLs contribute to neuronal injury in GABAergic circuits. We investigated whether selective CTL-mediated dysfunction of hippocampal interneurons may contribute to temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS). METHODS: We developed a mouse model based on virus-mediated expression of ovalbumin (OVA) selectively in CA1 hippocampal interneurons into transgenic mice harboring OVA-specific CD8+ T cells. This approach enables interneuron-specific immune targeting within the hippocampus. RESULTS: Interneuron-specific OVA expression in hippocampal CA1 resulted in rapid CD8+ T cell infiltration and targeting of inhibitory neuronal populations, accompanied by acute symptomatic seizures beginning 4 to 6 days after transduction. This acute inflammation-associated phase was followed by a chronic phase characterized by persistent spontaneous recurrent seizures (SRS), HS, sustained microglial activation, and astrogliosis. In the chronic stage, reduced Reelin expression coincided with interneuron vulnerability, granule cell dispersion (GCD), and mossy fiber reorganization. Proliferation analyses suggest that GCD results from displacement of pre-existing granule cells rather than aberrant neurogenesis, and is associated with gliosis and reduced Reelin expression. INTERPRETATION: These findings demonstrate that selective CTL-mediated targeting of hippocampal CA1 interneurons induces seizures and hippocampal remodeling. This model shapes current concepts of epileptogenesis by showing that cell type-specific autoimmune mechanisms recapitulate key features of TLE, including GCD. ANN NEUROL 2026.