# Glutamatergic plumes – a novel mechanism of excitability in the brain after TBI.

> **NIH NIH R21** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2022 · $168,427

## Abstract

PROJECT SUMMARY/ABSTRACT
Traumatic brain injury (TBI) is a major cause of mortality in both military and civilian populations. Meanwhile, TBI
survivors are at greater risk for long-term increases in brain network hyper-excitability. Despite the global burden
of TBI, there have been very few animal studies focused on mechanisms of excitability at synaptic and network
levels. Our goal is to dissect the potential mechanisms underlying TBI-associated excitability after mild and
severe brain injury. Recently, we observed an increased incidence of noncanonical glutamate release events,
known as glutamatergic plumes, 48 hours after TBI. Increased frequency of plumes can facilitate spreading
depolarization (SD) initiation. SD is an excitable phenomenon detected after TBI and is correlated with increased
tissue damage and poor outcome. Thus, the prevalence of plumes suggests that the network after TBI is
dysfunctional. We will examine this novel form of aberrant glutamate signaling in the brain, including the
consequences of plumes on post-TBI excitability. We will employ simultaneous in vivo whole-cell recording and
two-photon microscopy, alongside genetic tools to manipulate mechanisms of plumes. We will examine both
male and female mice, as females experience worse excitability-related complications post-TBI. In Aim 1, we
will determine the source of plumes in controlled cortical impact (CCI) and mild TBI models, and how those
mechanisms are altered in female mice. Based on our recent data, glutamate reuptake failure by astrocytes
facilitates plumes. Thus, we hypothesize that astrocytic clearance mechanisms are responsible for glutamate
plumes after TBI. To test this hypothesis, we will genetically ablate/enhance key astrocyte mediators of glutamate
clearance in vivo. These experiments will establish a precise mechanism of glutamate dysfunction (plumes) in
the post-TBI environment. In Aim 2, we will determine whether plumes can influence synaptic plasticity and
network dynamics. Our pilot data shows calcium loading is enhanced during spontaneous neuronal activity after
TBI. Based on current literature, glutamate dysfunction, such as increases in extracellular glutamate, can drive
calcium influx in the naïve brain. Since elevation in intracellular calcium is an important feature of long-term
potentiation (LTP) induction, we hypothesize that plumes in TBI drive brief but strong postsynaptic calcium
elevations contributing to LTP and thus to an increase in network excitability. This is important since aberrant
changes in synaptic plasticity are implicated in many neurological disorders. Notably, we will ask if and how
plumes after TBI induce plasticity in dendrites by performing two-photon imaging of dendritic calcium transients.
Furthermore, we will examine the mechanistic connection between plumes (and astrocytic mechanisms) and
SD-associated calcium load. We hypothesize that plumes provide the stimulus necessary for the activation of
NMDA receptors, th...

## Key facts

- **NIH application ID:** 11059782
- **Project number:** 7R21NS130541-02
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** PUNAM ADHIK POKAM
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $168,427
- **Award type:** 7
- **Project period:** 2022-09-21 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11059782

## Citation

> US National Institutes of Health, RePORTER application 11059782, Glutamatergic plumes – a novel mechanism of excitability in the brain after TBI. (7R21NS130541-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11059782. Licensed CC0.

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