# SV2A as a Therapeutic Target for Improved Neurotransmission after Traumatic Brain Injury

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $195,625

## Abstract

Project Summary
Impaired cognition is named as a major contributor to reduced quality of life in individuals living with a
traumatic brain injury (TBI). Neuronal communication and normal brain function require regulated
neurotransmitter release into the synaptic cleft. TBI results in impaired neurotransmitter release in multiple
brain regions and can contribute to motor and cognitive dysfunction following injury; however, little is known
about the mechanisms contributing to this impairment. Formation of the highly-conserved N-ethylmaleimide-
sensitive factor attachment protein receptor (SNARE) complex facilitates vesicular docking and release of
neurotransmitters, and reductions in SNARE complex formation are associated with impaired
neurotransmission. In experimental rodent models of TBI, SNARE complex formation is reduced and the
distribution of synaptic vesicles are altered in the weeks following injury. The synaptic vesicle glycoprotein 2A
(SV2A) is an important regulator of the synaptic pool of readily releasable vesicles and SNARE complex
formation. We have preliminary data that SV2A is reduced in synapses after TBI. SV2A was identified as the
binding site of the FDA approved antiepileptic drug Levetiracetam (Keppra) in the brain. Furthermore, the
Guidelines for Severe TBI cannot recommend Keppra without additional comparative studies. Keppra has
been shown in a small number of reports to promote improved neurobehavioral function in rodent models of
TBI, but the mechanism underlying this improvement is poorly understood. We have data showing treatment
with Keppra can improve SNARE complex formation after TBI. The overall hypothesis is that SV2A plays a role
in TBI-induced impaired neurotransmitter release, which can be restored with treatment of Keppra to improve
neurotransmission. Specific Aim 1 will determine the effect of TBI on SV2A abundance and SNARE complex
formation in glutamatergic and GABAergic pre-synaptic terminals. Specific Aim 2 will determine the effect of
Keppra treatment on SV2A abundance, SNARE complex formation, and high-potassium evoked
neurotransmitter release in the hippocampus after TBI. The contribution of SV2A in mediating the therapeutic
effects of Keppra will be tested in SV2A knockout mice. Successful completion of this project will provide
valuable insights into the understanding of synaptic dysfunction after TBI and potential benefits for clinical
usage of Keppra in TBI patients.

## Key facts

- **NIH application ID:** 10017359
- **Project number:** 5R21NS111099-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** SHAUN CARLSON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,625
- **Award type:** 5
- **Project period:** 2019-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017359

## Citation

> US National Institutes of Health, RePORTER application 10017359, SV2A as a Therapeutic Target for Improved Neurotransmission after Traumatic Brain Injury (5R21NS111099-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10017359. Licensed CC0.

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