Wednesday, April 2, 2025
4/2/2025
Noncanonical glutamate signaling in the origins of the migraine attack - 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 the accumulation of extracellular potassium and glutamate and thus to SD. We will test the hypothesis that plumes drive a barrage of postsynaptic activity that contributes to SD ignition. Finally we will test the hypothesis that this combination of reduced diffusion/reuptake and circuit excitability characteristics is what makes barrel cortex so susceptible to SD. If successful our work will help understand the mechanism of a completely novel form of glutamate signaling that is relevant not only to the migraine aura but to every neurologic disorder affected by SD. It will reveal the precise interplay of neuronal and astrocytic mechanisms involved in the induction of the SD wave. And it will delineate the mechanisms underlying the susceptibility of primary sensory cortex to aura.
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