# Inhibitory Network Plasticity in Neurological Disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $335,716

## Abstract

Project Summary: Temporal lobe epilepsy (TLE) develops in a third of over 300,000 patients with a first
seizure and over 30% of cases are resistant to drugs contributing to a significant disability. Presence of a
therapeutic time window between the initial insult and development of epilepsy suggests that improved
mechanistic understanding of early pathological process may enable prevention of epileptogenesis and
associated co-morbidities. While sclerosis of the hippocampal dentate gyrus characterizes late stage TLE, cell
loss, network reorganization and deficient inhibition in the dentate gyrus occur soon after insults that progress
to TLE. In particular, the dentate inhibitory gate which limits GC activity throughput is compromised early in
acquired TLE. However, what cells and circuits make up the dentate inhibitory gate and how this is
compromised after seizures is not fully understood. Recently, a new class of neurons, semilunar granule cells
(SGCs) were proposed as drivers of sustained dentate feedback inhibition. Although SGC-like neuros are
observed in multiple species including humans and are activated during behaviors, the development, molecular
identity, and connectivity of SGCs are not known making it difficult to determine their role in dentate function
and disease. The limited literature and our pilot data that SGCs input and output connections are distinct from
granule cells indicating that they play a unique role in dentate processing. This study will test the hypothesis
that SGCs from a parallel dentate circuit that strengthens inhibition in the normal brain. We further propose that
cellular and network changes after seizures compromise SGC mediated inhibition and augment their excitatory
effects contributing to epilepsy and memory deficits. Combining morphometry, Patch-seq transcriptomics,
electro- and optophysiology in transgenic mouse lines subject to experimental epilepsy and computational
modeling will allow us to test the above hypothesis. Aim 1 will define the cellular and circuit identity of SGCs
and determine molecular markers. Aim 2 will determine if the SGC excitatory circuit is strengthened and
feedback inhibitory circuit compromised after status epilepticus. Finally, Aim 3 will examine the normal and
seizure-induced development of SGCs and their contribution to dentate memory processing. On completion
the studies will eliminate specific knowledge gaps in how the dentate circuit functions in behaviors and
epilepsy, in keeping with the NINDS mission, and provide information needed to prevent collapse of dentate
inhibition soon after seizures and prevent development of epilepsy and memory co-morbidities.

## Key facts

- **NIH application ID:** 9908178
- **Project number:** 5R01NS069861-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Vijayalakshmi Santhakumar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,716
- **Award type:** 5
- **Project period:** 2011-09-30 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908178

## Citation

> US National Institutes of Health, RePORTER application 9908178, Inhibitory Network Plasticity in Neurological Disease (5R01NS069861-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9908178. Licensed CC0.

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