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Senescent Cell Clearance Ameliorates Temporal Lobe Epilepsy and Associated Spatial Memory Deficits in Mice
Tahiyana Khan1,2, David J McFall1,2, Abbas I Hussain2
1Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA.
Objective:
The pharmacological treatment of temporal lobe epilepsy (TLE), a disorder characterized by recurrent seizures and cognitive dysfunction, is limited to symptomatic control. Identifying novel targets to modify disease progression is of great clinical and translational interest. Cellular senescence has been recently implicated in the development and progression of other neurodegenerative diseases, but its role in TLE is unstudied.
Methods:
We first investigated cellular senescence markers in resected hippocampi from patients with medically intractable TLE through multiplexed immunofluorescence. We next used a mouse model of TLE (pilocarpine induced status epilepticus [SE]) for a combination of immunohistochemistry, behavioral testing, and electroencephalogram (EEG) monitoring. We implemented 2 strategies for removal of senescent cells (SCs), a genetic mouse model allowing for targeted senolysis, and a pharmacological approach using dasatinib and quercetin.
Results:
We found a 5-fold elevation of senescent glia in human TLE cases as compared with controls. In mice, we found increases in senescence markers at both the transcript and protein level and predominantly expressed in microglia, which developed within 2 weeks following SE. Senolytic treatment produced a 50% reduction in SCs, rescued long-term potentiation deficits, normalized spatial memory impairments, reduced seizures, and protected a third of animals from epilepsy.
Interpretation:
Our data demonstrate that SCs accumulate in both human TLE and in a mouse model of TLE and suggest that clearing SCs may be a viable strategy to reduce seizures and associated cognitive comorbidities. ANN NEUROL 2026;99:1059-1075.
Insights
Cellular senescence, a marker of aging cells, is elevated in temporal lobe epilepsy (TLE). Clearing these senescent cells (SCs) in mice reduced seizures and improved cognitive function, suggesting a new therapeutic target for TLE.
Area of Science:
- Neuroscience
- Cellular Biology
- Epilepsy Research
Background:
- Temporal lobe epilepsy (TLE) treatment focuses on symptomatic control, lacking disease-modifying strategies.
- Cellular senescence is implicated in neurodegeneration but its role in TLE remains unexplored.
Purpose of the Study:
- Investigate the role of cellular senescence in TLE.
- Determine if senescent cell clearance can ameliorate TLE pathology and symptoms.
Main Methods:
- Analyzed senescent cell markers in human TLE hippocampi using multiplexed immunofluorescence.
- Utilized a pilocarpine-induced mouse model of TLE for immunohistochemistry, behavioral tests, and EEG.
- Employed genetic and pharmacological (dasatinib/quercetin) senolysis to remove senescent cells.
Main Results:
- Human TLE cases showed a 5-fold increase in senescent glia compared to controls.
- Senescence markers increased in mice post-status epilepticus, primarily in microglia.
- Senolytic treatment reduced senescent cells by 50%, improved synaptic plasticity and memory, and decreased seizure frequency.
Conclusions:
- Senescent cells accumulate in human TLE and a TLE mouse model.
- Targeted clearance of senescent cells offers a potential therapeutic strategy for TLE and its cognitive comorbidities.
