Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in...

Mesial temporal lobe epilepsy (MTLE) is a prevalent form of focal epilepsy characterized by seizures originating from the hippocampus and adjacent regions. Neurostimulation presents an alternative for surgery-ineligible patients with intractable seizures. However, conventional approaches have limited efficacy and require refinement for better seizure control. While hippocampal low-frequency stimulation (LFS) has shown promising seizure reduction in animal studies and small clinical cohorts, its mechanisms, sex-specific outcomes, and long-term effects remain unknown.

We aimed to identify the antiepileptic and cognitive outcomes and potential underlying mechanisms of long-term hippocampal LFS in chronically epileptic male and female mice.

We used the intrahippocampal kainate mouse model replicating the features of MTLE: spontaneous seizures, hippocampal sclerosis, and memory deficits. During the chronic phase of epilepsy, we applied 1 Hz electrical LFS in the sclerotic hippocampus 6 h/day, four times/week for 5 weeks and examined its effects on epileptiform activity, spatial memory, and kainate-induced pathological features at cellular and synaptic levels.

Long-term hippocampal LFS consistently diminished focal seizures in epileptic male and female mice, with seizure reduction extending beyond the stimulation period. Additionally, long-term LFS relieved spatial memory deficits and reversed pathological modifications at perforant path-dentate granule cell synapses shortly after stimulation. LFS had no significant effect on secondarily generalized seizures, anxiety-like behaviour, neurogenesis, hippocampal sclerosis, or presynaptic vesicles in perforant path fibres.

These findings provide clinically relevant insights into the seizure type-specific effects of hippocampal LFS, which, alongside synaptic and behavioural improvements, could contribute to enhanced seizure control and quality of life in MTLE patients.