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Interneuron theta phase locking controls seizure susceptibility.

Zoé Christenson Wick1, Paul A Philipsberg1, Cassidy Kohler1

  • 1Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai; New York, 10029, United States.

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|September 18, 2025
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Summary
This summary is machine-generated.

Altering the timing of inhibitory neuron activity (theta phase locking) causally impacts seizure susceptibility. Restoring normal phase locking in epileptic mice reduced seizures, while disrupting it in healthy mice increased seizure risk.

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Area of Science:

  • Neuroscience
  • Epilepsy Research
  • Computational Neuroscience

Background:

  • Neuronal firing timing is crucial for brain function, organized by oscillations like theta.
  • Theta phase locking, where neurons fire at specific theta cycle phases, creates windows for information processing.
  • Disrupted theta phase locking is linked to neurological disorders, but its causal role is unproven due to technological limitations.

Purpose of the Study:

  • To develop a closed-loop optogenetic system (PhaSER) to control interneuron theta phase locking.
  • To investigate the causal role of inhibitory theta phase locking in seizure susceptibility.
  • To examine differences in theta phase locking between parvalbumin (PV+) and somatostatin (SOM+) interneurons in the dentate gyrus (DG) in epilepsy.

Main Methods:

  • Developed PhaSER, a closed-loop optogenetic system for precise control of interneuron phase locking.
  • Recorded theta phase locking profiles of PV+ and SOM+ interneurons in healthy and epileptic mouse models.
  • Utilized PhaSER to manipulate DG interneuron theta phase locking during seizure susceptibility tests.

Main Results:

  • PV+ and SOM+ interneurons exhibit distinct theta phase locking patterns in the DG.
  • Epileptic mice show dispersed PV+ interneuron activity across the theta cycle compared to healthy controls.
  • Restoring normal PV+ interneuron theta phase locking in epileptic mice decreased seizure susceptibility.
  • Disrupting normal PV+ interneuron theta phase locking in healthy mice increased seizure susceptibility.

Conclusions:

  • Provides the first causal evidence linking inhibitory theta phase locking to seizure susceptibility.
  • Demonstrates that precise control of inhibitory neuron timing can modulate network function in both healthy and epileptic brains.
  • Highlights the potential of targeting theta phase locking as a therapeutic strategy for epilepsy.