Using in vivo imaging technology, investigators at the University of Utah and the University of Padua have identified a new signaling mechanism for glutamate that was linked to the onset of spreading depression or spreading depolarization, a neuronal activity pattern that plays a role in multiple neurological disease states.
In mouse models of migraine, glutamate, which is the major excitatory neurotransmitter of the brain, was released in what the authors called "plumes" or puffs. Those puffs, which were the result of an imbalance between glutamate release by neurons and its clearance by astrocytes, set off spreading depression, and both the plumes and the depression could be induced by pharmacologically inhibiting glutamate reuptake by astrocytes.
The team reported its findings in the December 14, 2020, online issue of Neuron.
Glutamate content in the brain is highly regulated, because it is a double-edged sword. As the major excitatory neurotransmitter, glutamate signaling is critical to much of the brain's doing anything at all. But excessive levels of glutamate are highly toxic to neurons.
Previous work in the laboratory of co-corresponding author Daniela Pietrobon, who is a professor of physiology at the University of Padova, had identified an imbalance in glutamate release and reuptake in genetic mouse models of migraine.
In the work now published in Neuron, Pietrobon's lab collaborated with that of co-corresponding author K.C. Brennan "because in K.C.s lab, they had the opportunity... to measure these glutamate levels in vivo, in an awake animal," Pietrobon told BioWorld Science.
Brennan, who is a professor of neurology at the University of Utah, told BioWorld Science that the findings illustrate "the joyous role of serendipity in science... We had lovely-hypothesis driven research...'Let's show in the behaving animal what Daniela showed in the brain slice.' And the hypothesis came out correct... that was very successful, but quickly overwhelmed by these new events."
When lead author Patrick Parker, who was a graduate student in the Brennan lab at the time the research was conducted, first observed the plumes, "we thought it was a mistake," Brennan said.
Parker himself said in a prepared statement that "It wasn't exactly a 'eureka' moment. More like, 'What the heck was that?'"
The work suggests that "glutamate antagonist drugs that, if they are applied intelligently, could be deployed for prevention" of migraine, Brennan said. Both the anesthetic and antidepressant ketamine and the Alzheimer's drug memantine are glutamate receptor antagonists, and while ketamine is "way too strong for clinical use" in migraine at the doses used to treat treatment-resistant depression, "memantine is quite effective -- we use it for migraine with aura, but it's... effective for migraine without aura as well."
On the scientific side, "We want to know, at the greatest detail possible, what the molecular mechanisms of the plumes are," Brennan said. "What is the effect of plumes? Which receptors do they [activate] -- that question is very relevant to the development of therapeutics."
The researchers also want to "test the hypothesis that these events are occurring in other neurological diseases," Brennan said "We suspect very strongly, though we haven't proven it yet, that we will find these [plumes] in other neurological diseases."
Such research could lead to the development of new treatments for migraine, and possibly other neurological disorders where spreading depression occurs.
Certainly, the work gives new insights into the circuit malfunctions that underlie migraines, and "the more we know about how these migraine circuits work, the better we'll be able to develop unanticipated treatments," Brennan said.
Considering the prevalence of migraine, surprisingly little is known about those circuits.
What's pretty clear, though, is that early in a migraine attack, there is likely to be a dysfunctional neurological pattern called spreading depression or spreading depolarization.
Spreading depolarization is "one of the major excitatory events of the brain," Brennan explained, but one that has received less attention than its more spectacular cousin, the seizure.
"In terms of its dynamics, it's not what people think about" when they think about hyperexcitability, Brennan said.
While seizures are characterized by high, synchronized rates of neuronal firing, spreading depression is "a complete membrane depolarization, preceded by a brief period of high firing rate," Pietrobon said.
While a seizure "looks like an EKG gone crazy," Brennan said, a spreading depolarization takes the shape of "A large, mounding change in membrane potential" that stays changed for some period of time.
In migraine, that time period is relatively brief -- on the order of a minute, not enough time to do lasting damage to neurons. Longer-lasting spreading depression occurs in traumatic brain injury and stroke, where it contributes to neuronal damage and death.
In migraine, appears to be the neuronal phenomenon that underlies the sensory perception of an aura, changes in visual, auditory or tactile perception than occur in about a third of migraine attacks and provide a signal of impending pain when they do. As such, spreading depression is the earliest measurable feature of a migraine attack.
In animal models of migraine, spreading depression can directly activate the trigeminal nerve, which conveys pain perception in migraine. The link has not been directly demonstrated in humans, but "spreading depolarizations occur and we know phenotypically that patients who have had a verified spreading depression go on to have migraine pain," Brennan said.
Whether plumes would in any way lead directly to pain, or only through the intermediate of spreading depression, is not clear yet. Brennan said. But "what we can say for sure is that they are evidence of increased brain excitability in migraine patients... We do think of migraine as an excitability disease, but there's been very little hard evidence of that."