LINCs Are Vulnerable to Epileptic Insult and Fail to Provide Seizure Control via On-Demand Activation

Abstract

Temporal lobe epilepsy (TLE) is notoriously pharmacoresistant, and identifying novel therapeutic targets for controlling seizures is crucial. LINCs, a population of hippocampal neurons, were recently identified as a unique source of widespread inhibition in CA1, able to elicit both GABAA- and GABAB-mediated postsynaptic inhibition. We therefore hypothesized that LINCs could be an effective target for seizure control. LINCs were optogenetically activated for on-demand seizure intervention in the intrahippocampal kainate (IHKA) mouse model of chronic TLE. Unexpectedly, LINC activation at one month post-KA did not substantially reduce seizure duration in either male or female mice. We tested two different sets of stimulation parameters, both previously found to be effective with on-demand optogenetic approaches, but neither was successful. Quantification of LINCs following intervention revealed a substantial reduction of LINC numbers compared to saline-injected controls. We also observed a decreased number of LINCs when the site of initial insult (i.e. KA injection) was moved to the amygdala (BLA-KA), and correspondingly, no effect of light delivery on BLA-KA seizures. This indicates that LINCs may be a vulnerable population in TLE, regardless of the site of initial insult. To determine whether long-term circuitry changes could influence outcomes, we continued testing once a month for up to 6 months post-KA. However, at no time point did LINC activation provide meaningful seizure suppression. Altogether, our results suggest that LINCs are not a promising target for seizure inhibition in TLE.Significance StatementNovel treatments are needed for temporal lobe epilepsy, and altering inhibitory signaling may provide seizure control. Recently, a previously uncharacterized hippocampal cell population, LINCs, was found to provide strong, widespread, inhibition in healthy tissue. Despite being a novel source of powerful inhibition, and therefore a promising candidate for seizure control, on-demand activation of LINCs in a mouse model of temporal lobe epilepsy did not substantially suppress seizure activity. LINC numbers were decreased in epileptic tissue, indicating that LINCs are a vulnerable cell population. The heterogeneity of inhibitory signaling, and how it changes in epilepsy, are important factors to consider when developing new temporal lobe epilepsy therapies.

Early and widespread engagement of the cerebellum during hippocampal epileptiform activity Format: Brief Communication

“…The TTL pulses controlling the behavior and microscope cameras were simultaneously recorded, allowing for the alignment of the Hippocampal LFP data to the cerebellar imaging data. The timing of spontaneous behavioral seizures, electrographic events, and interictal spikes were determined offline using our custom in house software, as described previously 28,29,34,38,39 . Spontaneous overt, behavioral seizures were confirmed using the behavioral monitoring videos.…”