# Determining the role of dysregulated GABA uptake by reactive astrocytes in thalamic circuit hyperexcitability and seizures

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $42,071

## Abstract

PROJECT SUMMARY & ABSTRACT
 Acquired epilepsies can occur following brain lesions such as stroke or traumatic brain injury, and
particularly affects elderly people children. However, there is no effective treatment or prevention strategy
for post-traumatic epilepsy (PTE). Key to finding therapeutic targets is understanding epileptogenesis, the
latent period between the initial injury and the development of epilepsy. Reactive astrocytes, or astrogliosis,
form in response to neurological insults, and are strongly associated with epileptogenesis and with intractable,
drug-resistant, epilepsies. In order to understand how reactive astrocytes contribute to diseases characterized
by circuit abnormalities such as seizures, there is an urgent need to understand how they affect complex
neuronal activity.
 The thalamus has been implicated in PTE—following cortical injuries and stroke, the thalamus becomes
hyperexcitable, and develops chronic astrogliosis preceding the onset of seizures. Using a viral model of
selectively induced astrogliosis that I previously characterized, I will investigate the cellular and circuit
mechanisms by which reactive astrocytes drive circuit hyperexcitability in the thalamus and enable seizures. My
preliminary electrophysiological and transcriptomic studies have suggested a direct, mechanistic link between
astrocyte dysfunction and neural circuit hyperexcitability, in the context of inflammation. In this proposal, I will
test the working hypothesis that thalamic reactive astrocytes downregulate GABA uptake via reduction of
GABA transporters, which leads to enhanced tonic GABA currents in thalamocortical neurons, ultimately
resulting in thalamic circuit hyperexcitability and seizures.
 To test this hypothesis, I will characterize the effects of bidirectional manipulation of astrocytic GABA
uptake on GABAergic signaling in thalamocortical neurons, rhythmogenesis of the intrathalamic circuit in vitro,
and seizure susceptibility in awake, behaving mice. I will use a dual adeno-associated virus (AAV) CRISPR-
Cas9 approach to decrease astrocytic GABA transporter expression in wild-type mice (Aim 1), and an AAV-
mediated overexpression approach to selectively enhance astrocytic GABA transporter expression in wild-type
mice that have thalamic astrogliosis and abnormal thalamocortical hyperexcitability (Aim 2).
 The proposed work will harness the selectivity of the viral astrogliosis approach in combination with slice
and in vivo electrophysiological assessments of neuronal circuits. These results will elucidate our basic
understanding of astrocytic GABA uptake and neural circuit plasticity. Furthermore, by investigating the
functional changes in reactive astrocytes that enable pathological circuit activity and mediate epileptogenesis,
the proposed work will identify potential therapeutic targets to intervene and prevent PTE.

## Key facts

- **NIH application ID:** 10007592
- **Project number:** 5F31NS111819-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Frances Cho
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $42,071
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007592

## Citation

> US National Institutes of Health, RePORTER application 10007592, Determining the role of dysregulated GABA uptake by reactive astrocytes in thalamic circuit hyperexcitability and seizures (5F31NS111819-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10007592. Licensed CC0.

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