# Activity-dependent endocannabinoid control in epilepsy

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $567,401

## Abstract

Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome in adults. Current treatment options
for TLE remain often inadequate, as many patients suffer from uncontrolled seizures and negative treatment
side effects. Endogenous cannabinoid signaling involving the cannabinoid type 1 receptor (CB1) is
recognized to be a major presynaptic regulator of inhibitory neurotransmitter GABA release throughout the
CNS. However, although the therapeutic potential of endo- and exogenous cannabinoids has been
recognized for various neurological and psychiatric disorders, the in vivo mechanisms of cannabinoid
signaling remain poorly understood, limiting the effective design of novel therapies. Major reasons for our
incomplete understanding of cannabinoid signaling in the intact brain include the highly unstable nature of
lipid-derived cannabinoid ligands and the prior lack of methods to study CB1-expressing neurons in behaving
animals. Recently, we have introduced new tools that overcome these challenges, finally offering
researchers both the ability to detect fast lipid signals in the hippocampus of behaving mice, and to
selectively monitor and manipulate CB1-expressing GABAergic cells in vivo. Here, we propose to employ
these new tools to test the hypothesis that activity-dependent endocannabinoid dynamics in the intact
hippocampus are persistently modified in chronic TLE. We will then leverage novel, non-invasive, closed-
loop interventions to target CB1-expressing GABAergic cells in order to control chronic seizures and
ameliorate TLE-related disturbances in spatial information processing. We will test our hypothesis in
experimental mouse models of chronic TLE, utilizing a variety of innovative in vivo calcium-imaging,
electrophysiology, optogenetic and behavioral approaches. We anticipate that our project will have
significant, potentially translatable, impact by overcoming major knowledge gaps about activity-dependent
cannabinoid signaling in normal and epileptic neuronal circuits in behaving animals, and by accelerating the
development of non-invasive closed-loop intervention strategies.

## Key facts

- **NIH application ID:** 10809652
- **Project number:** 5R01NS131728-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Attila Losonczy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $567,401
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809652

## Citation

> US National Institutes of Health, RePORTER application 10809652, Activity-dependent endocannabinoid control in epilepsy (5R01NS131728-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10809652. Licensed CC0.

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