# Normal and Pathological Function of the Dentate Gyrus

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $568,054

## Abstract

The neuronal circuitry within the dentate gyrus is massively disrupted in temporal lobe epilepsy patients and in
experimental models of this disorder. This proposal builds upon our laboratory’s previous findings, which
demonstrate that the dentate gyrus circuitry within the epileptic hippocampus retains an embedded coding
network of dentate granule cells which can reemerge and restore appropriate cognitive function following
treatments to suppress degraded pathologic activity. The maintained competence of this embedded dentate
granule cell network occurs despite the significant structural pathology which is unaffected by therapeutic
interventions. In this proposal, we will build upon this foundation, and examine and manipulate dentate granule
cells in both epileptic and control animals to generate a mechanistic understanding of how these epilepsy-
associated disruptions to normal circuit functioning can be targeted to restore downstream, emergent
properties of the hippocampus, such as learning and memory and emotional behaviors. The CENTRAL
HYPOTHESIS of the present proposal is that the epilepsy-associated degradation in coding properties of
dentate granule cells contributes significantly to both the cognitive and behavioral comorbidities that constitute
key components of the core phenotypes of temporal lobe epilepsy. To test this Central Hypothesis, we propose
to conduct a series of experiments centered on 3 SPECIFIC AIMS: Aim 1. Characterize the local circuit
properties defining the active dentate granule cell network in epileptic and control mice. Aim 2. Determine the
capacity, time course, and extent of long-term dentate gyrus circuit specific intervention strategies to rescue
cognitive and behavioral function in epileptic mice. Aim 3. Assess the contribution of dentate granule cell
hyperexcitability in epileptic mice to disrupted hippocampal spatial coding. We know little about the
mechanisms that mediate the sparse yet deterministic firing properties of neuronal populations in the
hippocampal dentate gyrus that are responsible for their role in information coding and plasticity. We know
even less about how disease-associated degradation in these critical dentate granule cell properties develop,
and in turn how this excitability disruption may erode cognitive and affective functions that the hippocampus
normally supports. In addition to the enhanced excitability responsible for seizure generation, patients with
epilepsy exhibit severe cognitive comorbidities, including deficits in emotion, mood, and learning and memory,
processes typically thought of as limbic system functions. Understanding how epilepsy development alters the
basic circuit properties within the limbic system may be important not only in targeting new therapies for
seizure amelioration, but also in developing new treatments to reduce comorbid conditions accompanying
epilepsy development, a largely unexplored area of therapy development.

## Key facts

- **NIH application ID:** 10442117
- **Project number:** 2R01NS082046-10A1
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** DOUGLAS A COULTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $568,054
- **Award type:** 2
- **Project period:** 2012-09-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442117

## Citation

> US National Institutes of Health, RePORTER application 10442117, Normal and Pathological Function of the Dentate Gyrus (2R01NS082046-10A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10442117. Licensed CC0.

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