Illuminating the Cerebellum as a Potential Target for Treating Epilepsy

Commentary

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

Krook-Magnuson E, Szabo GG, Armstrong C, Oijala M, Soltesz I. eNeuro 2014;1(1):1–15.

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.

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 parvalbumin-expressing (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 most seizures in this model initiate in the ipsilateral hippocampus (relative to the site of KA injection), a subset of seizures can also arise from the contralateral hippocampus (10). In a previous study conducted by these investigators (9), optogenetic activation of hippocampal PV neurons, both ipsilateral and contralateral to the site of KA injection, resulted in comparable reductions in seizure duration. Similarly, seizure duration was decreased following optogenetic stimulation of ipsilateral and contralateral PV neurons (expressing channelrhodopsin or halorhodopsin) in the lateral cerebellar cortex. Furthermore, the magnitude of the reduction was comparable to what was observed following optogenetic activation of hippocampal PV-expressing interneurons. However, there was no change in seizure frequency (based on the interval between seizures) with interventions targeting either the lateral cerebellar cortex or hippocampus. Interestingly, excitation of PV-expressing neurons in the midline cerebellum significantly reduced both seizure duration and frequency, while inhibition of the midline cerebellum did not alter seizure frequency, indicating that the direction of modulation (excitation vs. inhibition) can influence seizure outcomes. Finally, the authors took advantage of the ability of optogenetics to target specific cell types and found that activation of Purkinje cells alone (the sole output of the cerebellar cortex) could similarly reduce both seizure duration and frequency.

This study confirms previous reports implicating a role for the cerebellum in the modulation of seizure activity. More specifically, the extent of seizure protection was shown to be influenced by 1) the target site within the cerebellum, and 2) the direction of modulation (activation vs. inhibition). Furthermore, targeting of the midline cerebellum or Purkinje cells alone were similarly capable of reducing seizure frequency and duration. The potential importance of the cerebellum as an epilepsy target, considering that optogenetic modulation of neuronal activity in the hippocampus (site of seizure generation), could reduce only seizure duration.

Notably, seizure occurrence in this study was based on electroencephalographic activity, rather than behavioral seizures. In a previous study by these authors (9), optogenetic modulation of hippocampal neurons in the MTLE mouse model was less effective at decreasing the number of behavioral seizures (29.6% reduction) compared with electroencephalographic seizures (37–57% reduction). Behavioral seizures were not examined in the current study; however, since targeting the cerebellum resulted in the amelioration of both seizure duration and frequency, it might also provide more robust protection against behavioral seizures. Additional studies will be required to determine whether targeting the cerebellum could provide protection against the neuronal loss and the behavioral deficits observed in MTLE. Based on this study, the cerebellum appears to be an attractive target for the modulation of epileptic activity, but caution should be exercised, given the importance of this brain region in coordination, motor learning and memory, and higher order cognitive functions.