Altered hippocampal interneuron activity precedes ictal onset

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Abstract

Although failure of GABAergic inhibition is a commonly hypothesized mechanism underlying seizure disorders, the series of events that precipitate a rapid shift from healthy to ictal activity remain unclear. Furthermore, the diversity of inhibitory interneuron populations poses a challenge for understanding local circuit interactions during seizure initiation. Using a combined optogenetic and electrophysiological approach, we examined the activity of identified mouse hippocampal interneuron classes during chemoconvulsant seizure induction in vivo. Surprisingly, synaptic inhibition from parvalbumin- (PV) and somatostatin-expressing (SST) interneurons remained intact throughout the preictal period and early ictal phase. However, these two sources of inhibition exhibited cell type-specific differences in their preictal firing patterns and sensitivity to input. Our findings suggest that the onset of ictal activity is not associated with loss of firing by these interneurons or a failure of synaptic inhibition, but is instead linked with disruptions of the respective roles these interneurons play in the hippocampal circuit.

Data availability

Source data files are included for each figure and supplemental figure. Raw data are too large (750Gb) to include within the manuscript but are available on request as compiled sets of raw data and intermediate analysis files.

Article and author information

Author details

Mitra L Miri

Department of Neuroscience, Yale University, New Haven, United States

Competing interests
The authors declare that no competing interests exist.
Martin Vinck

Department of Neuroscience, Yale University, New Haven, United States

Competing interests
The authors declare that no competing interests exist.
Rima Pant

Department of Neuroscience, Yale University, New Haven, United States

Competing interests
The authors declare that no competing interests exist.
Jessica Cardin

Department of Neuroscience, Yale University, New Haven, United States

For correspondence
jess.cardin@yale.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8209-5466

Funding

National Eye Institute (EY022951)

Jessica Cardin

National Science Foundation (Graduate Student Fellowship)

Mitra L Miri

Ford Foundation (Graduate Student Fellowship)

Mitra L Miri

Human Frontiers (Postdoctoral Fellowship)

Martin Vinck

Rubicon Fellowship (Postdoctoral Fellowship)

Martin Vinck

Whitehall Foundation (Research Grant)

Jessica Cardin

Alfred P. Sloan Foundation (Fellowship)

Jessica Cardin

Swebilius Foundation (Grant)

Jessica Cardin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All experiments were approved by the Institutional Animal Care and Use Committee of Yale University (#2015-11317).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.