Parvalbumin-expressing Inhibitory Theta Phase Locking in the Healthy and Epileptic Hippocampus Impacts Seizure Susceptibility
Abstract number :
3.047
Submission category :
1. Basic Mechanisms / 1C. Electrophysiology/High frequency oscillations
Year :
2024
Submission ID :
347
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Zoe Christenson Wick, PhD – Icahn School of Medicine at Mount Sinai
Paul Philipsberg, MS – Icahn School of Medicine at Mount Sinai
Cassidy Kohler, BS – Icahn School of Medicine at Mount Sinai
Sophia Lamsifer, BS – Icahn School of Medicine at Mount Sinai
Elizabeth Katanov, BS – Icahn School of Medicine at Mount Sinai
Yu Feng, PhD – Icahn School of Medicine at Mount Sinai
Lauren Vetere, PhD – Icahn School of Medicine at Mount Sinai
Denise Cai, PhD – Icahn School of Medicine at Mount Sinai
Tristan Shuman, PhD – Icahn School of Medicine at Mount Sinai
Rationale: Network-wide oscillations, such as theta, orchestrate and organize the spiking of individual neurons in a phenomenon known as phase locking. Phase locking has long been thought to maintain excitatory-inhibitory homeostasis and coordinate cognitive processes. We’ve recently found altered theta phase locking of inhibitory neurons in the dentate gyrus of epileptic mice with spontaneous seizures and cognitive deficits. While phase locking has been widely studied in a variety of contexts using correlational methods, the direct, causal influence of this phenomenon has never been determined. Thus, we aimed to directly test the hypothesis that inhibitory theta phase locking can bidirectionally control seizure susceptibility in control and epileptic mice.
Methods: To test this hypothesis, we developed a low-latency closed-loop optogenetic system (PhaSER) to bidirectionally control inhibitory phase locking to theta in head-fixed control and pilocarpine-treated epileptic mice navigating a virtual track. Using opto-tagging strategies, we first identified the preferred firing phase of parvalbumin (PV)+ and somatostatin (SOM)+ dentate interneurons in control and epileptic mice. We then applied our closed-loop system to lock the spiking of these dentate interneurons to their preferred or non-preferred phase of theta while measuring latency to seize after a systemic kainic acid injection.
Results: Using opto-tagging strategies, we found a cell-type specific deficit in theta phase-locking of PV, but not SOM neurons in the dentate gyrus of chronically epileptic mice. Furthermore, we have found that mis-aligning inhibitory spiking to the peak of theta increases seizure susceptibility in otherwise healthy, control mice and that re-aligning inhibitory spiking to the trough of theta diminishes seizure susceptibility in epileptic mice.
Conclusions: Together, these data suggest that theta phase locking of inhibitory spiking plays an important and causal role in seizure susceptibility. Gaining deeper insights into the impacts of inhibitory theta phase locking may reveal the potential of oscillation-driven stimulation as an effective epilepsy therapeutic, and the direct influence that inhibitory theta phase-locking holds over network-wide activity.
Funding: NIH F32 NS116416 (ZCW), Friedman Brain Institute Postdoc Innovator Award (ZCW), NIH R01 NS136590-01 (TS), CURE Taking Flight Award (TS)
Basic Mechanisms