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.