Cerebellar Directed Optogenetic Intervention Inhibits Spontaneous Hippocampal Seizures in a Mouse Model of Temporal Lobe Epilepsy

Abstract

Temporal lobe epilepsy is often medically refractory and new targets for intervention are needed. We used a mouse model of temporal lobe epilepsy, on-line seizure detection, and responsive optogenetic intervention to investigate the potential for cerebellar control of spontaneous temporal lobe seizures. Cerebellar targeted intervention inhibited spontaneous temporal lobe seizures during the chronic phase of the disorder. We further report that the direction of modulation as well as the location of intervention within the cerebellum can affect the outcome of intervention. Specifically, on-demand optogenetic excitation or inhibition of parvalbumin-expressing neurons, including Purkinje cells, in the lateral or midline cerebellum results in a decrease in seizure duration. In contrast, a consistent reduction in spontaneous seizure frequency occurs uniquely with on-demand optogenetic excitation of the midline cerebellum, and was not seen with intervention directly targeting the hippocampal formation. These findings demonstrate that the cerebellum is a powerful modulator of temporal lobe epilepsy, and that intervention targeting the cerebellum as a potential therapy for epilepsy should be revisited.

Selective Manipulation of Neural Circuits

“…After spinal cord injury [194,195], optical control of spinal neurons distal to the lesion could establish control of circuits that have been disconnected from brain control. In epilepsy [196][197][198], the goal has been to reduce cortical excitability, which can be accomplished with activation of inhibitory neurons or inactivation of excitatory ones.…”

Beyond the hammer and the scalpel: selective circuit control for the epilepsies

“…1). Similarly, seizure inhibition has been achieved using optogenetics in both acute models (including acute systemic lithium-pilocarpine in rat 23 and acute intrahippocampal bicuculline methiodide 24 or 4-Aminopyridine 25 in mouse) and chronic models (including stroke-induced thalamocortical epilepsy in rats 16 , tetanus toxin model of focal neocortical epilepsy in rat 26 , and intrahippocampal kainate model of temporal lobe epilepsy in mouse 18,27 ) (Fig. 2), in addition to inhibiting epileptiform activity in slices 24,28 and in silico 29 .…”

“…Optogenetic approaches can be used to study a variety of disorders, and a particular strength of the use of optogenetics for epilepsy research per se, especially when used in an on-demand manner, is the immediate read out available in the EEG. Despite the potential hurdles in the implementation of responsive systems, on-demand optogenetics has been successfully applied in models of thalamocortical 16 and temporal lobe epilepsies 18,27 (Figure 2). …”

“…An even more striking example of remote control of seizures comes from a recent study in which on-demand optogenetic intervention targeting the cerebellum inhibited seizures recorded from the hippocampus 27 . This study also reported a unique a reduction in seizure frequency (seen as an increase in time to next seizure), which was seen only with excitation of the midline cerebellum, and was therefore both location and direction of modulation sensitive.…”

“…However, the challenge remains to develop such an approach that could selectively target this population without having effects on other cell populations as well. Similarly, a region outside the seizure focus identified by optogenetics to modulate the frequency of seizures 27 could be targeted clinically with electrical stimulation. Again, however, this approach would lack the specificity of the newer technologies of optogenetics and DREADDs.…”