The glutamate mediates most of the excitatory synapses of the Central Nervous System (CNS). It is the main mediator of sensory, motor, cognitive and emotional information and intervenes in the formation of memories and their recovery, being present in 80-90% of synapses in the brain.

As if all this were not enough, it also intervenes in neuroplasticity, learning processes and is the precursor of GABA – the main inhibitory neurotransmitter in the CNS. What more can you ask of a molecule?

What is glutamate?

Possibly has been one of the most extensively studied neurotransmitters of the nervous system . In recent years its study has been increasing due to its relationship with various neurodegenerative diseases (such as Alzheimer’s disease), which has made it a powerful pharmacological target in various diseases.

It is also worth mentioning that given the complexity of its receptors, this is one of the most complicated neurotransmitters to study.

The process of synthesis

The process of glutamate synthesis begins in the Krebs cycle, or the tricarboxylic acid cycle. The Krebs cycle is a metabolic pathway or, to understand it, a succession of chemical reactions to produce cellular respiration in the mitochondria . A metabolic cycle can be understood as the mechanism of a clock, in which each gear performs a function and the simple failure of a part can cause the clock to break or not to mark the time properly. The cycles in biochemistry are the same. A molecule, by means of continuous enzymatic reactions -the gears of the watch-, changes its form and composition with the aim of giving rise to a cellular function. The main precursor of glutamate will be alpha-ketoglutarate, which will receive an amino group by transamination to become glutamate.

There is also another quite significant precursor: glutamine. When the cell releases glutamate into the extracellular space, astrocytes – a type of glial cell – recover this glutamate, which, through an enzyme called glutamine synthetase, will become glutamine. Then, the astrocytes release the glutamine, which is recovered again by the neurons to be transformed back into glutamate . And possibly more than one will wonder about this: And if glutamine has to be converted back into glutamate in the neuron, why does the astrocyte convert the poor glutamate back into glutamate? Well, I don’t know either. Maybe it’s that astrocytes and neurons don’t agree, or maybe it’s that Neuroscience is that complicated. In either case, I wanted to review astrocytes because their collaboration accounts for 40% of the glutamate turnover , which means that most of the glutamate is recovered by these glial cells .

There are other precursors and other routes by which glutamate is recovered and released into the extracellular space. For example, there are neurons that contain a specific glutamate transporter -EAAT1/2- that directly recover glutamate to the neuron and allow the excitatory signal to be terminated. For further study of glutamate synthesis and metabolism I recommend reading the literature.

Glutamate receptors

As we are often taught, each neurotransmitter has its receptors on the postsynaptic cell . The receptors, located in the cell membrane, are proteins to which a neurotransmitter, hormone, neuropeptide, etc., binds to give rise to a series of changes in the cell metabolism in which it is located at the receptor. In neurons we generally locate the receptors on the postsynaptic cells, although this does not have to be the case in reality.

We are also often taught in first grade that there are two main types of receptors: ionotropic and metabotropic. Ionotropics are those in which when their ligand – the “key” to the receptor – is attached, they open channels that allow the passage of ions into the cell. Metabotropics, on the other hand, when the ligand binds, cause changes in the cell by means of second messengers. In this review I will talk about the main types of glutamate ionotropic receptors, although I recommend the study of the bibliography for the knowledge of the metabotropic receptors. The main ionotropic receptors are listed below:

  • NMDA receiver.
  • AMPA receiver.
  • Kainado’s receiver.

NMDA and AMPA receptors and their close relationship

Both types of receptors are believed to be macromolecules formed by four transmembrane domains -that is, they are formed by four subunits that cross the lipid bilayer of the cell membrane- and both are glutamate receptors that will open cation channels -positively charged ions-. But, even so, they are significantly different.

One of their differences is the threshold at which they are activated. Firstly, AMPA receptors are much faster to activate; whereas NMDA receptors cannot be activated until the neuron has a membrane potential of about -50mV – a neuron when inactive is usually about -70mV. Secondly, the cation step will be different in each case. AMPA receptors will achieve much higher membrane potentials than NMDA receptors, which will collaborate much more modestly. In turn, NMDA receptors will achieve much more sustained activations over time than AMPA receptors. Therefore, AMPA receptors activate quickly and produce stronger excitatory potentials, but deactivate quickly . And those of NMDA take longer to activate, but manage to maintain the excitatory potentials they generate much longer.

To understand it better, let us imagine that we are soldiers and that our weapons represent the different receivers. Let’s imagine that extra-cellular space is a trench. We have two types of weapons: revolver and grenades. The grenades are simple and quick to use: you take off the ring, throw it away and wait for it to explode. They have a lot of destructive potential, but once you’ve thrown them all away, it’s over. The gun is a weapon that takes time to load because you have to remove the drum and put the bullets in one by one. But once we’ve loaded it we have six shots with which we can survive for a while, although with much less potential than a grenade. Our brain guns are NMDA’s receivers and our grenades are AMPA’s.

Excess Glutamate and its Dangers

They say that nothing is too good, and in the case of glutamate this is true. Next we will mention some pathologies and neurological problems in which an excess of glutamate is related .

1.Glutamate analogues can cause exotoxicity

Glutamate-like drugs, which perform the same function as glutamate, such as NMDA, after which the NMDA receptor is named , can cause high-dose neurodegenerative effects in the most vulnerable brain regions , such as the arcuato nucleus of the hypothalamus. The mechanisms involved in this neurodegeneration are diverse and involve different types of glutamate receptors.

2.Some neurotoxins that we can ingest in our diet exert neuronal death through excess glutamate

Different poisons from some animals and plants exert their effects through the glutamate nerve pathways. One example is the poisonous seeds of Cycas Circinalis, a poisonous plant that can be found on the Pacific island of Guam. This poison caused a high prevalence of Amyotrophic Lateral Sclerosis on this island where its inhabitants ingested it daily believing it to be benign.

3.Glutamate contributes to neuronal death from ischemia

Glutamate is the main neurotransmitter in acute brain disorders such as heart attack , cardiac arrest, pre/perinatal hypoxia. In these events where there is a lack of oxygen in the brain tissue, the neurons remain in a state of permanent depolarisation; due to different biochemical processes. This leads to the permanent release of glutamate from the cells, with subsequent sustained activation of glutamate receptors. The NMDA receptor is especially permeable to calcium compared to other ionotopic receptors, and excess calcium leads to neuronal death. Therefore, overactivity of glutamatergic receptors leads to neuronal death due to increased intraneuronal calcium.


The relationship between glutamate and epilepsy is well documented. Epileptic activity is thought to be particularly related to AMPA receptors, although as epilepsy progresses NMDA receptors become more important.

Is glutamate good? Is glutamate bad?

Usually, when one reads this type of text one ends up humanizing the molecules by putting labels on them of “good” or “bad” -this has a name and is called anthropomorphism , very fashionable there in medieval times-. The reality is far from these simplistic judgments.

In a society where we have generated a concept of “health” it is easy for some of nature’s mechanisms to make us uncomfortable. The problem is that nature does not understand “health”. We have created that through medicine, the pharmaceutical industry and psychology. It is a social concept, and like all social concepts it is subordinated to the progress of societies, whether human or scientific. Advances show that glutamate is related to a good number of pathologies such as Alzheimer’s or Schizophrenia. This is not an evil eye of evolution to the human being, rather it is a biochemical misadaptation of a concept that nature still does not understand: human society in the 21st century.

And as always, why study this? In this case I think the answer is very clear. Due to the role that glutamate has in various neurodegenerative diseases, it is an important – although also complex – pharmacological target . Some examples of these diseases, although we have not talked about them in this review because I think an entry could be written exclusively about them, are Alzheimer’s disease and Schizophrenia. Subjectively, I find the search for new drugs for schizophrenia particularly interesting for two basic reasons: the prevalence of this disease and the health costs involved; and the adverse effects of current antipsychotics which in many cases hinder therapeutic adherence.

Text corrected and edited by Frederic Muniente Peix

Bibliographic references:


  • Siegel, G. (2006). Basic neurochemistry. Amsterdam: Elsevier.


  • Citri, A. & Malenka, R. (2007). Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms.Neuropsychopharmacology, 33(1), 18-41.
  • Hardingham, G. & Bading, H. (2010). Señalización sináptica versus extrasináptica de los receptores NMDA: implicaciones para los trastornos neurodegenerativos. Nature Reviews Neuroscience, 11(10), 682-696.
  • Hardingham, G. & Bading, H. (2010). Señalización sináptica versus extrasináptica de los receptores NMDA: implicaciones para los trastornos neurodegenerativos. Nature Reviews Neuroscience, 11(10), 682-696.
  • Kerchner, G. & Nicoll, R. (2008). Silent synapses and the emergence of a post-synaptic mechanism for LTP. Nature Reviews Neuroscience, 9(11), 813-825.
  • Papouin, T. y Oliet, S. (2014). Organización, control y función de los receptores NMDA extrasinápticos.Philosophical Transactions Of The Royal Society B: Biological Sciences, 369(1654), 20130601-20130601.