# Anti-epileptogenic role of mTOR activation among hippocampal interneurons

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $492,803

## Abstract

PROJECT SUMMARY
 Epilepsy can be a debilitating and sometimes fatal disease for which there are no preventatives, no
cure, and for which existing medications fail in one third of patients. Development of preventative treatments
for epilepsy is a key NINDS goal (Benchmark II. Prevent epilepsy and its progression; Galanopoulou et al.,
2016; Binder et al., 2020). The mechanistic target of rapamycin (mTOR) pathway has emerged as a promising
target for epilepsy prevention. mTOR acts as a relatively ubiquitous promotor of cell growth; enhancing
neuronal connectivity, excitability and metabolism. Activation of the mTOR pathway occurs during
epileptogenesis and appears to regulate pro-excitatory changes implicated in the process. Moreover, blocking
mTOR signaling with the antagonist rapamycin mitigates epilepsy development in many epilepsy models.
Blocking mTOR signaling, however, does not work in all models, and there is evidence that this pathway may
also act to reduce brain excitability. To explain these conflicting effects, we hypothesize that increased mTOR
activation among excitatory neurons is pro-epileptogenic, while activation among GABAergic interneurons is
anti-epileptogenic. Systemic mTOR antagonists, therefore, block epileptogenic changes among excitatory
cells, but also block compensatory protective changes among interneurons. To test this hypothesis, we will use
intersectional genetic approaches to selectively delete the obligate mTOR regulatory proteins Raptor or Rictor
from vesicular GABA transporter-, parvalbumin-, and somatostatin-expressing interneurons in mice. We will
also examine the impact of enhancing mTOR signaling in interneurons by deleting the mTOR negative
regulator Tsc2. Studies will be conducted using both acquired and genetic models of epilepsy. We predict that
blocking mTOR signaling in interneurons will make epilepsy worse, while enhancing signaling will improve
outcomes. Studies will advance understanding of the role of mTOR in epileptogenesis and will have direct
implications for ongoing clinical use of mTOR antagonists.

## Key facts

- **NIH application ID:** 10362959
- **Project number:** 1R01NS121042-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Steve C Danzer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $492,803
- **Award type:** 1
- **Project period:** 2021-12-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10362959

## Citation

> US National Institutes of Health, RePORTER application 10362959, Anti-epileptogenic role of mTOR activation among hippocampal interneurons (1R01NS121042-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10362959. Licensed CC0.

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