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

TL;DR

A new mouse model of epilepsy with hippocampal damage was created by targeting specific brain cells, showing key features of human disease.

Contribution

A novel mouse model of MTLE-HS based solely on hippocampal GABAergic neuron loss is established.

Findings

Unilateral ablation of DG GABAergic neurons consistently induced spontaneous seizures.

Both DG and CA1 ablation models showed HS-like pathology and cognitive deficits.

The model exhibits sustained seizures and features distinct from traditional kainic acid models.

Abstract

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.

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.

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.

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.

A novel mouse model of mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) by unilateral, partial ablation of hippocampal GABAergic neurons is established. The model recapitulates key features of the human condition, including spontaneous recurrent seizures, HS‐like pathology, and associated cognitive deficits. It offers a targeted tool to study epileptogenesis driven by inhibitory neuron loss.

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