Massive "plumes" of glutamate, a key neurotransmitter, surging in the brain could help explain the onset of migraine with aura—and potentially a broad swath of neurologic disease, including stroke and traumatic brain injury—according to study led by University of Utah Health scientists.
The study, which was conducted in mice, found that an abnormal release of glutamate into the extra-cellular space can spark spreading depolarizations, tsunami-like waves of activity that spread across the brain in migraine and other nervous system disorders.
The finding was a bit serendipitous. Patrick Parker, lead author of the paper published today in Neuron, was studying abnormalities in glutamate signaling in mice carrying a human gene that leads to a condition called familial hemiplegic migraine type 2 (FHM2). Previous work in Italy found that the FHM2 mutation slows the rate of glutamate removal from the extracellular space, leading to excessive activity of brain networks. But what Parker and his team found in this current study was surprising: large plumes, or puffs of glutamate release, that appeared spontaneously and seemed to spread from a central location.
Intrigued, the researchers delved deeper, discovering that plumes arose from a dysfunctional interaction between neurons and astrocytes. The researchers determined that either too much neuronal release of glutamate, or too little astrocyte uptake, could lead to plumes.
Once the researchers better understood how plumes were generated, they wanted to know how these plumes affected brain disease. They found that a flurry of plumes preceded the onset of spreading depolarizations. Spreading depolarizations are not as well-known as seizures, but they are just as common, and under certain conditions, like stroke, subarachnoid hemorrhage, and traumatic brain injury, they can be just as damaging.
The team found that plumes predicted the onset of spreading depolarizations, and that preventing plumes inhibited them. "This shows that plumes don't just coincide with spreading depolarizations," lead author Patrick Parker explained. "They are involved in their generation."
Importantly, the scientists observed plumes before spreading depolarizations not only in FHM2 mice but also in normal control animals. This means that plumes are likely relevant well beyond migraine, where spreading depolarizations underlie the aura and trigger headache, Parker added.