Illuminating the Cerebellum as a Potential Target for Treating Epilepsy

Commentary Temporal lobe epilepsy (TLE) is most common form of refractory epilepsy, and mesial temporal lobe epilepsy (MTLE) is the most common subtype of TLE. MTLE is characterized by spontaneous seizures, behavioral abnormalities such as learning and memory deficits, and morphological changes in the hippocampus (e.g., neuron loss, mossy fiber sprouting) (1–3). At present, surgical resection of the seizure focus is the best treatment option; however, this invasive procedure can only be used in a subset of cases, identifying a critical need for the development of alternate treatments. Given the critical role of the hippocampus in TLE, this structure is considered the most obvious target for intervention. However, numerous projections extend to and from the hippocampus, suggesting that other brain regions might also make effective targets. In the current study, the cerebellum was evaluated as a potential therapeutic target for TLE. Several pieces of evidence provide support for the selection of the cerebellum. For example: 1) the cerebellum has been shown to influence hippocampal processing (4), and 2) direct connections between the cerebellum and hippocampus, via the midline of the cerebellum or nucleus fastigii, have been suggested as potential pathways for seizure regulation (5, 6). Optogenetics involves the use of light to excite or inhibit cells expressing channelrhodopsin or halorhodopsin, respectively. According to a recent review of optogenetics and epilepsy (7), a PubMed search of “optogenetics” conducted in August 2014 returned over 800 citations. As of June 2015, there are 1,201 citations for “optogenetics,” with 51 of these specifically for “optogenetics and epilepsy. ” A recent study by Krook-Magnuson et al., which is the focus of this commentary, used optogenetics to evaluate the cerebellum as a potential therapeutic target in the well-established intrahippocampal kainic acid (KA) mouse model of MTLE. This model, generated by injecting a low dose of KA into the dorsal hippocampus, recapitulates many features of human MTLE, including spontaneous seizures that typically begin 3 to 4 weeks after KA administration (8). Krook-Magnuson and colleagues used a closed-loop seizure detection system (9) to trigger the delivery of light to different sites within the cerebellum following the development of spontaneous seizures in the MTLE mouse model. Light was administered in response to 50% of detected electrographic seizures in a randomized manner, thereby enabling each animal to serve as its own control. Using this approach, the authors first demonstrated that seizure duration could be altered by either activation or inhibition of parvalbuminexpressing (PV) neurons in the lateral cerebellar cortex. Specifically, stimulating PV neurons expressing the excitatory channelrhodopsin (results in activation of PV neurons) or the inhibitory halorhodopsin (results in inhibition of PV neurons) resulted in a significant reduction in seizure duration. While Cerebellar Directed Optogenetic Intervention Inhibits Spontaneous Hippocampal Seizures in a Mouse Model of Temporal Lobe Epilepsy.