# Noncanonical glutamate signaling in the origins of the migraine attack

> **NIH NIH R37** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $707,843

## Abstract

PROJECT SUMMARY/ABSTRACT
 Migraine affects 15% of the world population, and is one of the leading causes of disability worldwide. Yet
surprisingly little is known about the basic features of this disease. One of the major questions in migraine is
how its quintessential feature, the migraine attack, is generated. For approximately a third of migraineurs, the
pain of the attack is preceded by an aura, typically a sensory hallucination. Unlike the attack, the aura is
physiologially measurable, in humans and in animal model systems, because its physiological correlate is a
massive cortical discharge called spreading depolarization (SD; also known as cortical spreading depression).
By understanding how SD is generated, we can understand how the attack begins. In our expiring award,
NS102978, we discovered events we call glutamate plumes: point-like glutamate discharges. Plumes occur
just prior to the onset of SD, generating a focus from which the wave arises, and suppressing plumes
significantly decreases the likelihood of SD induction. We thus identified a previously unknown proximate
mechanism in the induction of the migraine aura.
 But what causes plumes? The first aim addresses the subcellular mechanisms: In astrocytes, we will test
the hypothesis that depolarization underlies the failure in glutamate uptake required for plume generation. In
neurons, Calcium dependent neuronal vesicular release is the final step in plume generation. We will examine
extra- vs intracellular calcium sources to learn to what extent plumes represent truly noncanonical physiology,
vs. an exuberant form of normal synaptic transmission.
 We know that both astrocytes and neurons are required for plume generation, but we do not know
specifically how they interact, via what mediators, and in what sequence. In the second aim we examine the
interaction of neurons and astrocytes that we know is required for plume generation. We will use a combination
of fast two photon imaging, two photon linescan, and in vivo whole cell recording to determine the sequence of
neuronal and astrocytic activity that leads to plumes. Focal release of calcium, glutamate, and potassium with
uncaging techniques will help determine the minimum conditions necessary for plume induction. And we will
test the hypothesis that it is potassium released upon depolarization, rather than glutamate, that serves as the
primary agent of communication between the two cell types.
 Finally, How do plumes interact with other factors in the induction of SD? In the third aim, we examine the
mesoscale circuit level events required to generate SD. Novel potassium and voltage indicators will be used to
test the hypothesis that tonic increases in extracellular glutamate and potassium drive the more punctate
changes (plumes) that precede SD. Novel extracellular space indicators and diffusion measurements will help
test the hypothesis that the structural complexity of barrel cortex is a barrier to diffusion, contributing to th...

## Key facts

- **NIH application ID:** 10804412
- **Project number:** 2R37NS102978-06A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Kevin Christopher Brennan
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $707,843
- **Award type:** 2
- **Project period:** 2017-08-15 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804412

## Citation

> US National Institutes of Health, RePORTER application 10804412, Noncanonical glutamate signaling in the origins of the migraine attack (2R37NS102978-06A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10804412. Licensed CC0.

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