Key points: On-demand optogenetic inhibition of glutamatergic neurons in the fastigial nucleus of the cerebellum does not alter hippocampal seizures in a mouse model of temporal lobe epilepsy. In contrast, on-demand optogenetic excitation of glutamatergic neurons in the fastigial nucleus successfully inhibits hippocampal seizures. With this approach, even a single 50 ms pulse of light is able to significantly inhibit seizures. On-demand optogenetic excitation of glutamatergic fastigial neurons either ipsilateral or contralateral to the seizure focus is able to inhibit seizures. Selective excitation of glutamatergic nuclear neurons provides greater seizure inhibition than broadly exciting nuclear neurons without cell-type specificity. Abstract: Temporal lobe epilepsy is the most common form of epilepsy in adults, but current treatment options provide limited efficacy, leaving as many as one-third of patients with uncontrolled seizures. Recently, attention has shifted towards more closed-loop therapies for seizure control, and on-demand optogenetic modulation of the cerebellar cortex was shown to be highly effective at attenuating hippocampal seizures. Intriguingly, both optogenetic excitation and inhibition of cerebellar cortical output neurons, Purkinje cells, attenuated seizures. The mechanisms by which the cerebellum impacts seizures, however, are unknown. In the present study, we targeted the immediate downstream projection of vermal Purkinje cells – the fastigial nucleus – in order to determine whether increases and/or decreases in fastigial output can underlie seizure cessation. Though Purkinje cell input to fastigial neurons is inhibitory, direct optogenetic inhibition of the fastigial nucleus had no effect on seizure duration. Conversely, however, fastigial excitation robustly attenuated hippocampal seizures. Seizure cessation was achieved at multiple stimulation frequencies, regardless of laterality relative to seizure focus, and even with single light pulses. Seizure inhibition was greater when selectively targeting glutamatergic fastigial neurons than when an approach that lacked cell-type specificity was used. Together, these results suggest that stimulating excitatory neurons in the fastigial nucleus may be a promising approach for therapeutic intervention in temporal lobe epilepsy.
Bibliographical noteFunding Information:
This work was supported in part by The Winston and Maxine Wallin Neuroscience Discovery Fund Award, an American Epilepsy Society Postdoctoral Fellowship (M.L.S.), NIH R01-NS104071-01, a University of Minnesota McKnight Land-Grant Professorship award, and the University of Minnesota's MnDRIVE (Minnesota's Discovery, Research and Innovation Economy) initiative. The authors thank Chris Krook-Magnuson, Brandon McCollam and Jane Yap for technical assistance, Dr Michael Benneyworth and the University of Minnesota Mouse Behavior Core, the University of Minnesota University Imaging Centers, Dr Erin Larson and the University of Minnesota Optogenetics Core for technical assistance and equipment.
This work was supported in part by The Winston and Maxine Wallin Neuroscience Discovery Fund Award, an American Epilepsy Society Postdoctoral Fellowship (M.L.S.), NIH R01‐NS104071‐01, a University of Minnesota McKnight Land‐Grant Professorship award, and the University of Minnesota's MnDRIVE (Minnesota's Discovery, Research and Innovation Economy) initiative.
© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society
- fastigial nucleus
- temporal lobe epilepsy
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
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