Abstracts

Rationale: Many temporal lobe epilepsy (TLE) patients that are unresponsive to anti-epileptic drugs are also not good candidates for surgical resection, leaving a large population of patients with a great need for seizure control. On-demand optogenetics provides a powerful tool to study the potential influence of networks outside the hippocampus on temporal lobe seizures and thereby identify new targets for intervention. Recent work suggests that the cerebellum may exert surprising effects on physiological hippocampal function, opening up the possibility of cerebellar modulation of hippocampal function also in epilepsy. We therefore examined the potential for cerebellar directed optogenetic intervention to inhibit temporal lobe seizures. Methods: We used the intrahippocampal kainate mouse model of TLE to investigate the potential for cerebellar directed intervention to inhibit temporal lobe seizures. Chronic, spontaneous seizures were recorded from the hippocampus, and custom-designed software provided on-line seizure detection and closed-loop optogenetic intervention. Opsins were selectively expressed in parvalbumin containing neurons, including cerebellar Purkinje neurons. Results: Optogenetic activation of Purkinje neurons in the lateral cerebellar cortex produced a significant reduction in temporal lobe seizure duration (ipsilateral lobulus simplex: 40.2±8.69% seizure duration reduction; contralateral: 29.7±14.94% reduction; p<0.05). There was no significant change in time to next seizure (p=0.23) indicating the absence of a rebound effect, or a long-lasting inhibitory effect on seizures with lateral cerebellar light delivery. When light was instead delivered to the midline cerebellum (targeting the vermis), in addition to a reduction in seizure duration (38.6±14.4% duration reduction, p<0.05), there was a significant prolongation of the interseizure interval (175.3±63.9% increase in time to next seizure; p<0.05). This inhibition of seizure generation far outlasted the duration of the applied light, and was unique to vermal intervention in channelrhodopsin expressing animals. Optogenetic inhibition (rather than excitation) of Purkinje cells produced no significant effect on time to next seizure (percent change: -10.6±7.8%, p=0.16), indicating that activation of Purkinje cells is required to see this unique effect on seizure frequency. Conclusions: These data demonstrate that cerebellar activity can modulate temporal lobe seizures, with both the location of intervention and the direction of modulation being critical factors. On-demand optogenetic vermal stimulation not only truncated seizures, but also produced a unique reduction in seizure frequency which far outlasted the duration of intervention - an effect not observed even with direct hippocampal intervention. The need for new therapeutic approaches is clear, and our data provide strong support for reevaluation of cerebellar targeted intervention. Funding: US NIH grant K99NS087110 (EKM), the Epilepsy Foundation (CA), the George E. Hewitt Foundation for Medical Research (GS), US National Institutes of Health grant NS074432 (IS)