Ablation of Unilateral Hippocampal GABAergic Neurons: A Novel Mouse Model of Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis

AIMS: While various animal models of mesial temporal lobe epilepsy (MTLE) exist, a validated model based solely on hippocampal GABAergic interneuron loss is lacking. We aimed to establish and characterize a novel MTLE with hippocampal sclerosis (HS) model by selective ablation of these neurons. METHODS: Using AAV vectors (flex-DTA or DIO-taCasp3-TEVp), we performed unilateral, partial ablation of GABAergic neurons in the dentate gyrus (DG) or CA1 subregions of VGAT-Cre mice. Spontaneous recurrent seizures (SRS) were monitored by video-EEG. Behavioral tests and histopathological analyses were conducted to assess comorbidities and HS features. RESULTS: DG-ablated mice all developed SRS, whereas 50%-70% of CA1-ablated mice did. Lethal SRS occurred in around 50% of DG-ablated mice. Both ablation models exhibited sustained SRS from Days 8-28, distinct from kainic acid model severity in some parameters. The model recapitulated anxiety-like behaviors, cognitive deficits, and hallmark HS pathology including gliosis, granule cell dispersion, and mossy fiber sprouting. CONCLUSION: Selective unilateral hippocampal GABAergic interneuron loss is sufficient to drive chronic epilepsy with HS. This model provides direct causal evidence and a precise platform for investigating MTLE-HS mechanisms and therapies.