# Interneuron-based mechanisms of temporal lobe epilepsy

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $570,924

## Abstract

Project Summary / Abstract
Epilepsy affects 1 in 26 Americans over the course of a lifetime. Temporal lobe epilepsy is one of the most
common types. Medical treatment fails in one-third of patients. Development of effective therapies is limited by
gaps in knowledge about how spontaneous seizures begin. Determining how spontaneous seizures initiate in
temporal lobe epilepsy is our long-term goal. The primary goal of the proposed project is to test the hypothesis
that seizures start, at least in part, because inhibitory interneurons reduce their action potential firing frequency
(deactivate), which reduces inhibitory control of excitatory neurons. Aim 1 is to test whether interneuron
deactivation is seizure specific. Local field potential recordings from many brain regions in epileptic pilocarpine-
treated rats would be used to identify sites of seizure initiation. Simultaneous unit recordings of hippocampal
interneurons would be evaluated to test whether interneuron deactivation is more frequent and severe in
epileptic versus control rats and at seizure onset sites versus non-onset sites. Aim 2 is to test whether
preventing interneuron deactivation prevents seizures. Local field potential recordings from many brain regions
would be used to identify rats in which the ventral hippocampus is the seizure focus. Closed-loop activation of
interneurons would prevent deactivation at sites of seizure onset. Optogenetics and Cre-dependent
channelrhodopsin-expressing viral vectors in glutamic acid decarboxylase-Cre and parvalbumin-Cre transgenic
rats would be used to selectively activate specific interneuron subtypes. Optogenetic stimulation would be
triggered by real-time detection of rapid eye movement sleep, which precedes many seizures in rat models of
temporal lobe epilepsy. Aim 3 is to test whether deactivating interneurons causes seizures. The experimental
approach would be similar to that of Aim 2, except the novel Cl--conducting opsin SwiChR++ would be used to
deactivate interneurons. Our deactivation hypothesis is opposite of others that contend that hyperactivity of
interneurons is a mechanism of seizure initiation. The proposed project would rigorously test multiple
hypotheses of temporal lobe ictogenesis and advance understanding of how spontaneous seizures start.

## Key facts

- **NIH application ID:** 10558603
- **Project number:** 5R01NS107290-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** PAUL S. BUCKMASTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $570,924
- **Award type:** 5
- **Project period:** 2019-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10558603

## Citation

> US National Institutes of Health, RePORTER application 10558603, Interneuron-based mechanisms of temporal lobe epilepsy (5R01NS107290-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10558603. Licensed CC0.

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