# Astrocytic Glutamate Transporter 1 (GLT-1) enhancement for the treatment of seizures in Dravet Syndrome

> **NIH NIH R21** · BOSTON CHILDREN'S HOSPITAL · 2021 · $486,750

## Abstract

Project Summary:
Epilepsy is a common, multifactorial neurological disorder affecting approximately 1% of the population.
Mutations in voltage-gated sodium channels are responsible for several monogenic epilepsy syndromes, and
heterozygous loss-of-function mutations in the SCN1A gene result in Dravet syndrome (DS), a severe infant-
onset disease characterized by intractable seizures, developmental delays and increased mortality. While the
DS phenotype, as in all monogenic epilepsies, expresses variably among individuals with the same mutation
(suggesting that genetic or environmental modifiers may influence clinical severity), the resultant seizures are
often resistant to conventional antiepileptic drugs (AEDs), some of which in fact exacerbate seizures in this
disorder. Thus, a novel therapeutic AED target in DS is highly desirable.
We and others have identified suboptimal removal of the excitatory neurotransmitter glutamate from synapses
due to reduced expression of astrocytic glutamate transporter (GLT-1) as a contributor to acquired and
congenital epilepsy, both in rodents and humans. Notably, GLT-1 (termed excitatory amino acid transporter 2,
EAAT2 in humans) expression, when depressed, can be enhanced by common beta lactam antibiotics
(unrelated to these compounds' antimicrobial properties), and we identified that treatment with ceftriaxone, a
member of the β-lactam class with good blood-brain barrier penetrance, suppresses seizures in a rat acquired
epilepsy model. Relevant to DS, we documented a clinical observation where children with DS experience
seizure suppression when exposed to beta lactam antibiotics. In parallel, in a DS SCN1A haploinsufficiency
(Scn1a+/-) mouse model, we identified that GLT-1 protein is depressed in cortex and hippocampus, which
raises prospects for GLT-1 deficiency as a plausible novel therapeutic target in DS.
Accordingly, we propose a set of exploratory experiments aimed to (1) test the clinical utility of GLT-1
enhancement by ceftriaxone (or analogous compound) in DS treatment. (2) test whether GLT-1 reduction is an
Scn1a+/- endophenotype, or the product of recurrent seizures, and (3) characterize the developmental
regulation of GLT-1 expression in the Scn1a+/- mouse.
Given that seizures in DS do not respond to conventional AEDs, our proposed experiments will be the first step
toward a novel adjunctive antiepileptic treatment in this devasting syndrome. Beyond DS, the proposed
experiments will provide insight into the role of astrocytic glutamate transport in milder variants of SCN1A
haploinsufficiency, and in other epilepsies. As GLT-1 upregulation may be accomplished by safe and
inexpensive drugs, we anticipate that favorable results from the proposed studies will translate rapidly to
human trials in DS or in related disorders.

## Key facts

- **NIH application ID:** 10288936
- **Project number:** 1R21NS123459-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Alexander Rotenberg
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $486,750
- **Award type:** 1
- **Project period:** 2021-09-30 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288936

## Citation

> US National Institutes of Health, RePORTER application 10288936, Astrocytic Glutamate Transporter 1 (GLT-1) enhancement for the treatment of seizures in Dravet Syndrome (1R21NS123459-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10288936. Licensed CC0.

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