# Neuronal Circuit Mechanisms of Epileptogenesis

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $558,510

## Abstract

ABSTRACT Temporal lobe epilepsy is the most prevalent and least therapeutically responsive form of
epilepsy in the adult population. In addition to the spontaneous seizures that define the condition, temporal
lobe epilepsy is associated with significant cognitive and emotional comorbidities, and this triad of symptoms
defines its devastating consequences in patients. Clearly, based on its prevalence, distressing symptomology,
and lack of adequate control by existing medications, a better mechanistic understanding of this disorder is
critical in improving this dire clinical outlook. Many hippocampal alterations are associated with temporal lobe
epilepsy development, with the most prevalent being pathologic hyperactivation of the dentate gyrus. Although
these diverse hippocampal circuit changes accompany the clinical condition, which disruptions causally
contribute to the symptoms underlying epilepsy is not known. To determine this, it is necessary to move
beyond observational studies and to evaluate a causal linkage. This can be accomplished by reversing a
specific circuit change experimentally and looking for restorative effects on seizure susceptibility, cognition,
and emotional state—proving a change is necessary for full manifestation of epilepsy. Similarly, it is also
essential to establish that mimicking the circuit change in normal animals (in the absence of any other
alteration) is able to induce the same set of hallmark epilepsy symptoms—proving that a change is sufficient to
generate changes in seizure predisposition, cognition, and emotional state. Our CENTRAL HYPOTHESIS
driving the research in this application is that epilepsy-associated dentate gyrus hyperexcitability generates the
enhanced seizure susceptibility, disrupted cognition, and emotional disturbances that are the hallmark
symptoms of epilepsy. We plan to test this hypothesis through experiments centered on 3 AIMS. These aims
are: AIM 1: Determine the role played by epilepsy-associated dentate granule cell hyperexcitability in
generation of the elevated seizure susceptibility underlying both the development and expression of epilepsy.
AIM 2: Characterize the role played by epilepsy-associated dentate granule cell hyperexcitability in
compromised cognitive performance and elevated anxiety in an animal model of temporal lobe epilepsy. AIM 3:
Assess the role played by epilepsy-associated dentate granule cell hyperexcitability in deficient spatial
encoding in the hippocampus. Dentate gyrus hyperexcitability is seen both in animal models as well as in
patients. Successful completion of this proposed research should provide a definitive assessment of the role
played by this prevalent epilepsy-associated circuit disruption in the generation of the core triad of epilepsy
symptoms. Understanding the causal contributions of circuit changes generating epilepsy is critical in
understanding the key processes mediating epilepsy development, which in turn is necessary in developing
new the...

## Key facts

- **NIH application ID:** 10103855
- **Project number:** 5R01NS038572-19
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** DOUGLAS A COULTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $558,510
- **Award type:** 5
- **Project period:** 1999-05-06 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10103855

## Citation

> US National Institutes of Health, RePORTER application 10103855, Neuronal Circuit Mechanisms of Epileptogenesis (5R01NS038572-19). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10103855. Licensed CC0.

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