# Mechanisms of Hippocampal Pattern Separation Deficits in Epilepsy

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $477,349

## Abstract

Project Summary/Abstract
 Following an initial seizure, only some individuals develop temporal lobe epilepsy (TLE) but few methods
exist to predict individual risk 1,2. Thus there is a pressing need to identify biomarkers and predisposing conditions
for epileptogenesis. This pilot study aims to test our central hypothesis that vulnerability of the dentate gyrus
(DG) predisposes individuals for epileptogenesis. TLE shares symptoms with other disorders (e.g.Alzheimer's
disease (AD), autism spectrum disorder (ASD), schizophrenia and tuberous sclerosis), not only including
seizures with temporal lobe foci but also problems with memory and navigation, confusion and social
impairments 3-15. All of these diseases share pathology in the DG including cell loss, aberrant axonal sprouting,
neurogenesis and inhibitory circuitry. The DG is part of the hippocampal formation in the temporal lobe, and is
critical for navigation, episodic memory and acts as a "gate" or "filter" that limits propagation of excessive
excitation passing from cortex to downstream hippocampal areas 16-18. The DG is hypothesized to be the main
locus of the computational function of "pattern separation" that re-encodes similar memories into less similar
output in order to a) avoid confusion between overlapping patterns and b) avoid hyperexcitation 19-22. Malfunction
of pattern separation could therefore simultaneously result in epilepsy and associated cognitive problems.
However, until recently, pattern separation has been studied exclusively through theoretical models or by
behavioral assays, with no experimental demonstration that DG itself is the pattern separator. To remedy this
knowledge gap, we developed a novel brain slice model in which patterns are fed into the DG via perforant path
stimulation and their separation is quantified by measuring DG output 24. Thus, pattern separation can be
observed in isolated hippocampal tissue, providing an accessible platform for dissecting its underlying
mechanisms and possible failure during TLE. Here, we will use two well-studied mouse strains that have low
(C57Bl/6) and high (DBA/2J) susceptibility to kainate-induced status epilepticus (SE) 27,28, in combination with
behavioral testing, video-EEG and patch clamp electrophysiology in slices, to address the following Specific
Aims: (1) - Determine the relationship between pattern separation memory, electrographic activity and circuit-
level pattern separation. (2) - Determine key mechanisms contributing to circuit-level pattern separation and how
they are altered in epilepsy. Comparison of DG-mediated pattern separation memory and DG circuit physiology
between low- and high-susceptibility strains (with and without an insult) will reveal whether baseline differences
in DG function are associated with a predisposition to seizures and whether changes in DG function correlates
with epileptogenesis.
1

## Key facts

- **NIH application ID:** 9958802
- **Project number:** 1R21NS116546-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** MATHEW V JONES
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $477,349
- **Award type:** 1
- **Project period:** 2020-05-01 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9958802

## Citation

> US National Institutes of Health, RePORTER application 9958802, Mechanisms of Hippocampal Pattern Separation Deficits in Epilepsy (1R21NS116546-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9958802. Licensed CC0.

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