A recent report in Cell details a new way that the brain synthesizes glutamate, originating from sun exposure, no less. The research raises the question, do we really know how the brain makes one of its most important neurotransmitters?
Why do so few non-neuroscientists know what glutamate is?
I recently found myself among non-neuroscientist friends discussing MSG. In case you’re unfamiliar, MSG is a delicious food additive that was commonly used in Chinese-American restaurants until regulators became concerned that the ingredient caused symptoms like nausea, headaches, and flushing when overconsumed. The evidence linking MSG to these symptoms is weak and a double-blind placebo-controlled study found no evidence for the so-called Chinese restaurant syndrome.1 I chimed in that the logic behind MSG syndrome didn’t even make sense to me since MSG is just glutamate salt. I said “your body knows how to regulate glutamate since it’s probably the most important neurotransmitter in your brain”. I was met with blank stares. That’s when I realized that glutamate doesn’t have a particularly good publicist.
To be fair to glutamate’s hypothetical marketing team, the job of selling glutamate to the public hasn’t always been easy. First, glutamate wasn’t truly established as a neurotransmitter until the 1980s, decades after more widely known neuromodulators like dopamine and serotonin. Indeed, the 1950s, 60s, and 70s were a period of neurotransmitter mania. Dopamine loss was shown to cause Parkinson’s disease. The original antidepressant medications were shown to alter brain serotonin and norepinephrine levels. A link between schizophrenia and dopamine was established. This era culminated in the concept of neurochemical imbalances, the idea that psychiatric illnesses are caused by improper neurotransmitter levels in the brain. Consequently, neurotransmitters got tidy functional descriptions like “dopamine is rewarding” that were cemented into the popular imagination of the brain. Glutamate, partly because it missed this era, but also because it’s too ubiquitous to all brain functions, has never been pinned with a neat functional description that the public could easily digest.
While Nobel prizes were handed out for work on norepinephrine and dopamine, neuroscientists debated if glutamate even served a specialized function in the brain, at all. Glutamate was already known as an essential amino acid, a building block of proteins. Glutamate was also known to be a component of the Krebs cycle, the sequence of reactions responsible for producing cellular energy in the form of ATP. So every cell in our body, not just neurons, has a lot of glutamate floating around, participating in many non-neurotransmission things. You could say that glutamate was hiding in plain sight from mid-century neuroscientists. It was abundant, ubiquitous, and busy serving other functions. No single experiment proved that glutamate was a transmitter. It took decades of incremental progress to establish glutamate’s neurotransmitter bona fides. Drugs that looked a lot like glutamate seemed to have profound effects on neurons in a dish. Different types of glutamate receptors were discovered and their contributions to neuronal function were delineated through incremental progress.2 By the 1980s, overwhelming experimental evidence pointed to glutamate as not only a true neurotransmitter, but the brain’s most common messenger in neuron-to-neuron communication.
Today, the things that happen within the few nanometers of a glutamatergic synapse are the obsession of whole fields of neuroscience. That being said, glutamate, itself, is rarely placed at the center of the narrative. In contrast to the 50s-70s, today’s neuroscience casts circuits (ensembles of connected neurons), rather than transmitters, as the central characters in the brain. Today we are told that circuits are the conduit for how we learn, think, and feel. Even though most of these circuits require glutamate neurotransmission, glutamate itself is not the star of the show. Instead, it’s cast as a small piece of the bigger puzzle that is the neural circuit.
Do we really know how glutamate is made?
A question often asked about neurotransmitters is, how do they get made? In the 50s-70s, neurotransmitter origin stories were the intensely studied. Biochemical maps of dopamine and serotonin synthesis were drawn into text books and are still a popular quiz subject in introductory neuroscience courses. How your brain’s glutamate gets made, though, has never quite had a satisfying answer. The most recognized mechanism for brain glutamate synthesis is actually not synthesis at all but recycling. Specialized brain cells called astrocytes take a breakdown product of glutamate, glutamine, and reconvert it to glutamate before shuttling it back to neurons. So glutamate comes from old glutamate, which begs the question where does the original glutamate come from? To this question, the answer seems to be a shrug. Perhaps it comes from the Krebs cycle or from broken down proteins or from diet. A study published in the May issue of Cell introduces a new idea, what if it comes from the sun?3
Authors from The University of Science and Technology of China used a novel, sensitive way to measure chemicals within single neurons. With this technique, the authors found a handful of chemicals that have never been measured before in neurons, one of which is something called urocanic acid. Though no one’s seen it in the brain before now, urocanic acid has an interesting role in the skin, where it is thought to act like a natural sunscreen by absorbing UV rays. In fact, urocanic acid levels in the skin actually increase with prolonged sun exposure. So, the authors wondered if brain urocanic acid has anything to do with this skin urocanic acid system. They exposed mice (after a quick buzz cut) to UV-B rays, a type of UV ray emitted by the sun. Surprisingly, urocanic acid increased inside neurons after a few hours of UV-B exposure to the skin.
So, exposure to UV-B elevates urocanic acid in the skin and bloodstream, which gets into your brain and elevates the levels of urocanic acid inside neurons. What does this have to do with glutamate? In the liver, there’s an enzyme that can convert urocanic acid to glutamate. Up until now, no one really considered whether this enzyme is in the brain and active. The authors probed for it, found it, and showed that this enzyme is responsive to changes in urocanic acid. So along with increasing urocanic acid, UV-B exposure actually increases glutamate levels nearly 3-fold (!) inside neurons. The last real question the authors had to answer is whether or not this increase in glutamate affects brain functions. The authors presented two pieces of evidence suggesting that it does. First, they saw stronger, more robust, synaptic transmission in the hippocampus, a brain region associated with learning and memory, in mice exposed to UV-B. Last, they assessed two different learning paradigms in live mice, following UV-B exposure. They showed that mice exposed to UV-B were better at both motor learning (behaviors like balance and coordination) and recognition memory (behaviors like learning and recalling new objects).
Again, so how does the brain make glutamate?
This study, utilizing a new way to detect trace chemicals within neurons, stumbled into a novel way the mammalian brain makes one of its most important transmitters. Since mice are nocturnal, it’s a bit peculiar that UV-B rays produce such profound, glutamate-elevating effects. We don’t really know if humans get a sun-triggered boost in glutamate to the same degree as the mice in these experiments, who are experiencing UV-B rays for the first time. Though another question that one might propose is whether diurnal mammals, because they’re outside during daylight, produce more neuronal glutamate than nocturnal mammals like mice. One can’t help but think about the evolutionary trade-off between the safety of a nocturnal lifestyle and the boost in brain capacity provided by sun exposure. Perhaps nocturnal mammals like mice get by on subsistence levels of glutamate, derived from the Krebs cycle. Sun exposure, on the other hand, unlocks a potent driver of glutamate synthesis, boosting, perhaps even tripling, glutamate levels and neuronal signaling capacity in diurnal mammals like us. While these are merely suggestions at this point, it’s intriguing to think that such fundamental aspects of glutamate neurotransmission are still unknown. That should be expected, though, since glutamate – despite being one of the single most important chemicals in the brain – has never really been cast in a dynamic role.
1 Tarasoff, L. & Kelly, M. F. Monosodium L-glutamate: a double-blind study and review. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 31, 1019-1035 (1993).
2 Zhou, Y. & Danbolt, N. C. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm (Vienna) 121, 799-817, doi:10.1007/s00702-014-1180-8 (2014).
3 Zhu, H. et al. Moderate UV Exposure Enhances Learning and Memory by Promoting a Novel Glutamate Biosynthetic Pathway in the Brain. Cell 173, 1716-1727 e1717, doi:10.1016/j.cell.2018.04.014 (2018).
Sam Rose received his PhD in Neuroscience from Emory University. He is currently a postdoctoral scholar at Duke University (Durham, North Carolina). His research focuses on the role of G-protein coupled receptors in various neuropsychiatric disorders. You can email him at firstname.lastname@example.org