Abstracts

Rationale: Despite being canonically considered a motor control structure, the cerebellum is increasingly recognized for important roles in processes beyond this traditional framework, including seizure suppression. Excitatory fastigial neurons project to a large number of downstream targets, and it is unclear if this broad targeting underlies seizure suppression, or if a specific output may be sufficient.

Methods: In the present study, we utilized the mouse unilateral intrahippocampal kainic acid model of temporal lobe epilepsy, a dual viral approach for targeting specific fastigial output channels, and on-demand optogenetics to determine which fastigial outputs were responsible for seizure suppression.

Results: We find that output from the fastigial nucleus occurs via distinct output channels, in which fastigial neurons that project to the superior colliculus, medullary reticular formation, and central lateral nucleus of the thalamus comprise largely non-overlapping populations. In addition, these three populations send collaterals to unique sets of other thalamic and brainstem regions. We found that neither optogenetic stimulation of superior colliculus nor reticular formation output channels attenuated hippocampal seizures. In contrast, on-demand stimulation of fastigial neurons targeting the central lateral nucleus robustly inhibited seizures.

Conclusions: Our results indicate that fastigial control of hippocampal seizures does not require the simultaneous modulation of many fastigial output channels. Rather, selective modulation of the fastigial output channel to the central lateral thalamus, specifically, is sufficient for seizure control. This may provide a means for more selective therapeutic interventions, which provide seizure control while minimizing unwanted side effects.

Funding: Please list any funding that was received in support of this abstract.: This work was supported in part by The Winston and Maxine Wallin Neuroscience Discovery Fund Award, an American Epilepsy Society Postdoctoral Fellowship (MLS), NIH R01-NS112518, a University of Minnesota McKnight Land-Grant Professorship award, and the University of Minnesota’s MnDRIVE (Minnesota’s Discovery, Research and Innovation Economy) initiative.