Abstracts

Rationale: Mesial temporal lobe epilepsy (MTLE) is a common medically refractory neurological disease. Deep brain electrical stimulation (DBS) of grey matter has been used for MTLE with limited success. However, stimulation of a white matter tract connecting the hippocampi, the ventral hippocampal commissure (VHC) in rodents with low frequencies has shown promising results with seizure reduction greater than 98% in bilateral hippocampi (Toprani and Durand, 2013a). Similar results were obtained in an acute model of status epilepticus (Tang and Durand, 2012) and in a chronic rat model of epilepsy (Rashid et al, 2011) and in patients during 4-h periods of low frequency stimulation (Koubeissi et al, 2013). Therefore determination of the mechanisms would allow optimization the parameters. Methods: In order to study the mechanisms involved in the suppression, a novel in vitro slice preparation containing bilateral hippocampi connected by the VHC was used to test the hypothesis that electrical stimuli could induce hyperpolarization lasting hundreds of ms. We then applied electrophysiology and pharmacology to study the mechanisms. Results: Stimulus-induced long-lasting-hyperpolarization (LLH) could be mediated by GABA_B inhibitory post-synaptic potentials (IPSP) or slow after-hyperpolarization (AHP). GABA_B blockers and/or sAHP antagonists diminished stimulus-induced hyperpolarization concurrently with LFS efficacy (greater than 50% reduction). Blocking both the GABA_B IPSP and sAHP simultaneously eliminated the effect of electrical stimulation on seizure reduction entirely. Conclusions: These data show that LFS of the VHC is an effective paradigm for bilateral hippocampal seizure reduction and that its efficacy relies on the induction of long-lasting hyperpolarization mediated through GABA_B IPSP and sAHP. These results indicate that low frequency stimulation of fiber tracts can induce a decrease in the excitability of neural tissue leading to seizure suppression. Since these tracts affect a large volume of brain tissue, the suppression could be widespread leading to a novel method of seizure control in patients with temporal lobe epilepsy.