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

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Temporal lobe epilepsy (TLE) is notoriously pharmacoresistant, and identifying novel therapeutic targets for controlling seizures is crucial. Long-range inhibitory neuronal nitric oxide synthase-expressing cells (LINCs), a population of hip-pocampal neurons, were recently identified as a unique source of widespread inhibition in CA1, able to elicit both GABAA-mediated 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 in-trahippocampal 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 suc-cessful. 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 months post-KA. However, at no time point did LINC activation provide meaningful seizure sup-pression. Altogether, our results suggest that LINCs are not a promising target for seizure inhibition in TLE.

Original languageEnglish (US)
Article numberENEURO.0195-22.2022
Issue number2
StatePublished - Feb 2023

Bibliographical note

Funding Information:
This work was funded by National Institutes of Health Grant R01-NS-104071 (to E.K.-M.), the University of Minnesota McKnight Awards (E.K.-M.), a University of Minnesota Informatics Institute-MnDRIVE (Minnesota’s Discovery, Research, and Innovation Economy initiative) Informatics Graduate Assistantship (B.J.S.), and a MnDRIVE Research Fellowship in Neuromodulation (B.J.S.).

Publisher Copyright:
© 2023, Society for Neuroscience. All rights reserved.


  • channelrhodopsin
  • closed-loop
  • GABAergic
  • interneuron
  • nNOS
  • responsive neurostimulation

PubMed: MeSH publication types

  • Journal Article


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