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Long-range inhibitory neuronal nitric oxide synthase-expressing cells (LINCs), a population of hippocampal neurons, were recently identified as a unique source of widespread inhibition in CA1, able to elicit both GABA<jats:sub>A<\/jats:sub>-mediated and GABA<jats:sub>B<\/jats:sub>-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 (KA) mouse model of chronic TLE. Unexpectedly, LINC activation at 1 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 with 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 [basolateral 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\u2009months 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.<\/jats:p>","DOI":"10.1523\/eneuro.0195-22.2022","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T18:50:18Z","timestamp":1675277418000},"page":"ENEURO.0195-22.2022","source":"Crossref","is-referenced-by-count":2,"title":["LINCs Are Vulnerable to Epileptic Insult and Fail to Provide Seizure Control via On-Demand Activation"],"prefix":"10.1523","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8030-6805","authenticated-orcid":false,"given":"Bethany J.","family":"Stieve","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madison 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