# The Role of Raptor in Temporal Lobe Eplieptogenesis

> **NIH NIH F31** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $39,433

## Abstract

Project Summary
Despite availability of anti-epileptic drugs, one-third of the 3.4 million US patients with epilepsy have medically
intractable epilepsy and still experience seizures despite treatment. There are no effective treatments to
prevent the development of this debilitating condition (antiepileptogenic) in at-risk patients.
The mechanistic target of rapamycin (mTOR) pathway, which regulates neuronal plasticity and growth, has
emerged as a promising candidate for the development of anti-epileptogenic therapies. Pharmacological
antagonists of the mTOR pathway have shown efficacy at preventing seizure occurrence in animal models of
epilepsy, however, the cellular targets and signaling complexes mediating these effects are unclear.
Hippocampal dentate granule cells (DGCs) may be prime targets of mTOR mediated pathological changes
seen in temporal lobe epilepsy (TLE). mTOR signaling is increased among DGCs during the development of
TLE, and treatment with rapamycin can block the formation of atypical DGC morphology. Our lab has shown
that deletion of mTOR inhibitor, phosphatase and tensin homolog (PTEN) from newborn hippocampal dentate
granule cells (DGCs) resulted in the mossy fiber sprouting and soma hypertrophy associated with epilepsy.
These abnormalities exhibited in DGCs are thought to be associated with breakdown of the dentate gyrus’
ability to filter incoming information from the entorhinal cortex, creating hyper-excitable hippocampal circuits,
resulting in spontaneous recurrent seizures. We hypothesize that rapamycin produces its diseasing modifying
effects by blocking mTOR signaling in DGCs. To test this hypothesis, we will genetically delete the essential
mTORC1 adaptor protein raptor from granule cells in a mouse TLE model and determine whether the
treatment reduces seizure incidence and prevents dysmorphogenesis in DGCs (Aim 1). To assess the role of
raptor in epileptogenesis, we have developed a viral strategy in which LoxP-flanked raptor can be deleted after
pilocarpine-induced status epilepticus by injecting transgenic animals with AAV9.CamKII.HI.eGFP-Cre. Cre-
mediated recombination in hippocampal neurons will lead to the deletion of raptor, preventing mTORC1 activity
in these cells. (Aim 2) We predict that blocking hippocampal DGCs plays a role in the pathogenesis of TLE.
Our proposal leverages collaborative, conceptual, and methodological innovation to make meaningful progress
towards delineating the roles of mTORC1 and mTORC2 in the pathogenesis of epilepsy. The results, together
with mentored training, will provide a foundation for working toward new solutions for epilepsy and other
neurological disorders.

## Key facts

- **NIH application ID:** 10299626
- **Project number:** 5F31NS115525-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Christin Margaret Godale
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,433
- **Award type:** 5
- **Project period:** 2019-12-01 → 2022-06-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10299626

## Citation

> US National Institutes of Health, RePORTER application 10299626, The Role of Raptor in Temporal Lobe Eplieptogenesis (5F31NS115525-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10299626. Licensed CC0.

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