As much as we like to think of ourselves as discoverers and inventors, often enough nature has a way of unraveling itself in fortuitous circumstances. Jeffrey Watkins, a neurochemist who worked on describing glutamate’s role in the brain, notes on why he chose to focus on it from a vast list of chemicals:
“Sodium glutamate was top of the list because of the high concentration of glutamic acid in brain, and because we had a 500 g bottle on the shelf!” 1
GABA, the main inhibitory neurotransmitter in the brain, was already known in the 1950s, when these studies were taking place. Seeing how glutamate has a very similar structure, the first assumption was that it too must act as an inhibitory agent. This hypothesis was, however, quickly ruled out, and it ended up taking more than 15 years to figure out what role glutamate plays in the brain.
What does glutamate do?
Glutamate is coined as the primary excitatory neurotransmitter in the brain. This means that once it is released at a synapse, it binds to its receptors and excites the neuron. What ‘excitation’ translates to depends on the neuron. It is estimated that over 90% of all synapses contain glutamate receptors. 2 Some of its most impressive effects include a role in memory, neuronal development and synaptic plasticity.3,4
Why is there so much of it?
One curious feat of glutamate is just how abundant it is in the brain – in fact, it is the most abundant amino acid, at 0.7- 2.5 g / kg brain tissue, depending on the region.
Do we need so much for signaling purposes? Not at all. In fact, for a long time, it was thought that all neurotransmitters should only be available in the brain in minute concentrations, since it’s hard to explain something ubiquitous having such precise effects. Much of the reason it took so long for glutamate to be viewed as a neurotransmitter is that there is so much of it in our brain, and it does have other purposes.
One of the first scientists to give glutamate a role was Hans Adolf Krebs, the 1953 Nobel Laureate, who discovered the citric acid (or Krebs) cycle. This complicated biochemical process is what turns food (glucose, fats) to a form of energy cells can use – ATP. While glutamate is not technically a part of it, it can be converted to one of the intermediaries, and thus serve as an energy source. 5
Not only this, but glutamate can also be a starting point for protein synthesis and even help with oxidative stress. It constitutes the substrate GABA is made from. Outside the brain, it promotes muscle growth, helps the kidneys maintain our blood pH, and sustains various vital biochemical processes. 6 Artificially added in food, it produces the elusive umami taste. Given its many different roles, no wonder any cell (neurons included) needs to have a good amount of it. But if it is so widely-used, how can it be a neurotransmitter – send a specific signal to a neuron?
This is because the neurotransmitter role is not so much a function of the substance itself, but rather of having specific receptors to bind to, that then send the information about its presence downstream. 5
The glutamate receptors
Glutamate has so many different receptors that we had to divide them into families. Much like family names, their titles don’t exactly roll off the tongue. The way they were classified was based on what other amino acids, besides glutamate, can significantly activate the receptor. This is how we got: NMDA receptors, AMPA receptors, and kainate receptors.
Despite their different names and structures, they have two things in common: they bind glutamate, and they are ion channels (or ionotropic receptors). What this means is that once their ligand (be it glutamate, or a more specific synthetic one like NMDA or AMPA) binds to them, they open and allow particular ions to flow in or out of the cell.
Unlike GABA receptors, which are primarily chlorine channels by definition, all these glutamate receptors are rather non-specific. They allow cations to flow through, with Na + and others such as Ca2+ flowing in and K+ often flowing out, by virtue of their respective concentration gradients. The end result of this flow is exciting the neuron. These receptors are fast-acting and thought to be involved in signal transmission.
The story gets less straightforward if we consider another glutamate receptor family – the so-called metabotropic receptors. They are not ion channels; they act slowly and through entirely different mechanisms once glutamate binds to them. What is particularly interesting is that their net effect is not necessarily excitatory. Depending on their subtype, they can either increase or decrease a neuron’s excitability, giving rise to a wide variety of physiological effects.7
Much like with GABA, it was found that glutamate receptors don’t only sit at synapses, but also on other parts of the neurons- the so-called extra-synaptic glutamate receptors. 11 It is also worth noting that glutamate receptors can be found in tissues other than the brain, even on cells that don’t do much signaling. For example, tumor cell proliferation can be glutamate-dependent, as well as insulin release from pancreatic cells and bone formation.8
How much is too much?
If we’ve seen that glutamate is so abundant within the nervous system, how comes that neurons are not in a permanent state of excitation? The brain deals with this much in the same way we deal with an overwhelming day: compartmentalization.
Not all the glutamate inside a cell acts as a neurotransmitter. In order to play this role, glutamate must be encased into synaptic vesicles, brought close to the membrane, and released at the synaptic cleft. Only then can glutamate act on its designed receptors. Even this action time is very much limited as it gets quickly caught back into the neuron and adjacent glial cells. For an even finer degree of control, all the processes of getting into a vesicle or back into one cell or another are finely regulated by specific channels called glutamate transporters.9
Too much glutamate stimulation can quite literally excite nerve cells to their death. Excitotoxicity is what ensues when a cell gets stimulated past its tolerance.5
Short-term, this is thought to be the mechanism of lathyrism – a neurological disease caused by eating certain vegetables (Lathyrus genus). One of the oldest neurotoxic disorders known to man, it is characterized by tremors, weakness, and ultimately irreversible paralysis of the lower limbs that follows the ingestion of large quantities of these vegetables. The actual neurotoxin is β-N-oxalyl-amino-l-alanine, a substance very similar to glutamate.10
Long-term, several lines of evidence link glutamate excitotoxicity with neurodegeneration. Abnormally high levels of excitation are thought to rely not on the glutamate inside the neuron, but rather on that floating around outside of it (in the extracellular fluid). Typically, these glutamate concentrations outside the cell should be kept extremely low, thousands of times lower than inside the cell. Various deficits either in the glutamate release or clearing mechanisms can lead to a higher than average concentration, which can prove exhausting. 11
Excitotoxicity has been associated with a variety of neurological diseases, such as Alzheimer’s, Huntington’s, and ALS, as well as neuropsychiatric disorders. Massive, acute releases of glutamate can also lead to excitotoxicity – related cell death in strokes, traumatic brain injury and severe epilepsy. 11
If we were to sum up Glutamate and GABA, it would be fair to say that they serve as some form of balance. Equilibrium is key. Too much or too little of any of them is detrimental, which is why complicated regulation systems are required to keep them in check. Grasping this balance and placing it in the overall context of brain physiology is of essence in both understanding the healthy brain and treating the ailing one.
Watkins, J. C. & Jane, D. E. The glutamate story. British Journal of Pharmacology 147, S100 (2006).
Samardzic, J., Jadzic, D., Hencic, B., Jancic, J. & Strac, D. S. Introductory Chapter: GABA/Glutamate Balance: A Key for Normal Brain Functioning. in GABA And Glutamate - New Developments In Neurotransmission Research (InTech, 2018). doi:10.5772/intechopen.74023
McEntee, W. J. & Crook, T. H. Glutamate: its role in learning, memory, and the aging brain. Psychopharmacology 111, 391–401 (1993).
Moretto, E., Murru, L., Martano, G., Sassone, J. & Passafaro, M. Glutamatergic synapses in neurodevelopmental disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry 84, 328–342 (2018).
Zhou, Y. & Danbolt, N. C. Glutamate as a neurotransmitter in the healthy brain. Journal of Neural Transmission 121, 799–817 (2014).
Newsholme, P., Procopio, J., Ramos Lima, M. M., Pithon-Curi, T. C. & Curi, R. Glutamine and glutamate - Their central role in cell metabolism and function. Cell Biochemistry and Function 21, 1–9 (2003).
Glutamate Receptors - Neuroscience - NCBI Bookshelf. Available at: link. (Accessed: 1st May 2020)
Nedergaard, M., Takano, T. & Hansen, A. J. Beyond the role of glutamate as a neurotransmitter. Nat. Rev. Neurosci. 3, 748–755 (2002).
Kandel, E., Schwartz, J., Jessell, T., Siegelbaum, S. & Hudspeth, A. J. Principles of Neural Science. (Elsevier, 2012).
Manna, P. K., Mohanta, G. P., Valliappan, K. & Manavalan, & R. Lathyrus and Lathyrism: A review. Int. J. Food Prop. 2, 197–203 (1999).
Lewerenz, J. & Maher, P. Chronic glutamate toxicity in neurodegenerative diseases-What is the evidence? Frontiers in Neuroscience 9, 469 (2015).