Glutamate: A Biochemical Exciting Neurons for Better Memory and Learning
Optimizing this excitatory neurotransmitter can improve cognitive function and mental health, yet its dysfunction can cause severe health issues.
Watch Out for Glutamate Dysfunction!
Glutamate is a critical and paradoxical biochemical. In proper amounts and at the right times, glutamate can improve cognitive function, mental health, and physical performance. Excitement is a great feeling, but too much of it is not good for the body and mind.
Both excessive and deficient amounts can cause impairment of the cognitive, neural, endocrine, and immune systems, leading to severe neurological and mental health disorders, as I summarize in this article, linking to credible sources.
This post aims to briefly introduce glutamate as a critical amino acid and biochemical and highlight the severe impact of this neurotransmitter’s dysfunction in the brain and the nervous system. I introduced other neurotransmitters that interact with glutamate in previous articles.
Health conditions and lifestyle factors might cause glutamate dysfunction, as I will cover in the final section of this story. The critical contributors to this undesirable situation are neurodegenerative diseases, traumatic brain injury, stroke, infections, genetic mutations, excessive alcohol use, and substance abuse.
What is glutamate?
Glutamate is an amino acid and also biochemical in nerve cells. It acts as a neurotransmitter in the brain and central nervous system.
As a neurotransmitter, it is critical for stress response, memory building, improving the learning process, appetite, metabolism, and homeostasis (balance) of the brain.
Unlike GABA, glutamate stimulates and excites the neurons, making them more active for various purposes, such as improving cognitive performance, memory formation, alertness, and increased mental energy. 90% of excitatory functions in the brain are caused by glutamate.
Glutamate’s interaction with GABA can provide a better brain and nervous system balance. An enzyme called glutamate dehydrogenase can break it down for a balanced release in the brain and nervous system.
But glutamate also interacts with other neurotransmitters like dopamine, serotonin, oxytocin, acetylcholine, norepinephrine, adrenaline, histamine, and endocannabinoids for memory formation, attention, alertness, arousal, learning, pain perception, and mood management.
In a nutshell, glutamate has three primary functions in the brain: synaptic transmission for electrical signals, triggering electrical responses in the postsynaptic neurons, and maintaining homeostasis in the brain by balancing the levels of excitation and inhibition.
As informed in this paper, “the finding of glutamate receptors throughout the gastrointestinal tract has opened up a new vista in glutamate function. The great bulk of dietary glutamate is catabolized within the intestine. Glutamate interaction with specific taste cells in the tongue is a major component of umami taste.”
The paper emphasizes that “post-translational carboxylation of glutamyl residues increases their affinity for calcium and plays a significant role in homeostasis. Glutamate is necessary to synthesize key molecules, such as glutathione and polyglutamated folate cofactors.”
In the right amount, glutamate is essential for physical and mental vitality. Both too much or too little glutamate in the nervous system cause severe problems. Like other hormones and neurotransmitters, the body regulates glutamate tightly.
As this recent review paper documented, “There is little consensus on the best way to measure glutamate. Glutamate is present at higher concentrations than GABA. However, difficulties separating it from glutamine and glutathione have been highlighted.”
How does the body create, release, and use glutamate?
The primary source of glutamate is the amino acid glutamine that we consume from plant- and animal-based protein sources. This amino acid is abundant in the body, such as tissues and the bloodstream.
In addition to its dietary abundance, the recycling process is another reason it is so abundant. The body keeps recycling glutamine converting it to glutamate and vice versa. The glial cells in the brain perform this action.
Glutamate is produced in the body through transamination. It involves transferring one molecule to another. Specifically, the amino group from glutamine is transferred to another molecule, alpha-ketoglutarate, to form glutamate.
The body uses glutamate for other purposes, such as a precursor for synthesizing other amino acids. For example, the enzyme pyrroline-5-carboxylate converts glutamine to proline, and argininosuccinate synthase converts it to arginine.
When glutamate is created by nerve cells, it is stored in synaptic vesicles at the end of each nerve cell, including many other neurotransmitter molecules. So vesicles are critical to storing and releasing neurotransmitters to bind to specific receptors in the brain.
Glutamate acts differently than other neurotransmitters in the brain. For example, it can bind to four different receptors intensifying its stimulating effect in the nerve cells and creating excitation in the brain.
Even though glutamate does not have a direct hormonal impact on the body, it can indirectly affect hormones, primarily through the HPA axis, regarding stress response and energy balance.
Associated Disorders for Glutamate Dysfunction
In excessive amounts for a prolonged time, its overstimulation of neurons can cause excitotoxicity, impair cognitive function, and lead to severe disorders such as neurodegeneration, as observed in Alzheimer’s and Parkinson’s patients.
Furthermore, as documented in this systemic review, excessive levels of glutamate in the brain are linked to increased pain sensations. Some studies mention chronic pain such as fibromyalgia, low back pain, and migraines.
For example, this 2018 study proposed glutamate and its receptors as therapeutic targets for migraine as there is substantial evidence indicating a role for glutamate in migraine. Levels of glutamate are higher in the brain and peripheral circulation in migraine patients, particularly during attacks.
The paper informed that “population genetic studies implicate genes involved with glutamate signaling in migraine, and gene mutations responsible for familial hemiplegic migraine and other familial migraine syndromes may influence glutamate signaling.”
Overall literature indicates that severe glutamate deficiency in the brain and the nervous system might result in poor communication leading to anxiety, depression, schizophrenia, and autism. I’d like to share a few papers covering and explaining these conditions to give you an idea.
A 2022 study on MDPI identified links between disturbances in the glutamatergic system and autism spectrum disorder (ASD).
The paper informs that “glutamate-centered theories of ASD are based on evidence from patient samples and postmortem studies, as well as studies documenting abnormalities in glutamatergic gene expression and metabolic pathways, including changes in the gut microbiota glutamate metabolism in patients with ASD.”
In addition, the paper pointed out that “preclinical studies on animal models have demonstrated glutamatergic neurotransmission deficits and altered expression of glutamate synaptic proteins.”
A 2019 study found evidence for glutamatergic dysfunction and impaired energy metabolism in schizophrenia patients using magnetic resonance spectroscopy. The paper explained the impact and implication of glutamate dysfunction for neuropsychiatric disorders.
Another 2019 paper published on Neuron related to depression informed that “studies of the neurobiological basis of alterations have focused on both the principle, excitatory glutamate neurons, and inhibitory GABA interneurons. They demonstrate structural, functional, and neurochemical deficits in both major neuronal types that could lead to signal integrity degradation in cortical and hippocampal regions.”
As this 2022 paper highlights, “several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is a predominant excitatory neurotransmitter where the astrocytes play a pivotal role in maintaining the extracellular levels through release and uptake mechanisms.”
The authors of the paper conclude that “the optimum regulation of astrocytic glutamatergic transmission could pave the way for managing neurodegenerative disorders and add to their therapeutic value.”
Glutamate dysfunction is also linked to traumatic brain injury, ALS (Amyotrophic Lateral Sclerosis), and MS (Multiple Sclerosis). As my father died from ALS, I conducted intense research on this deadly disease which has no cure yet.
As this paper points out, “30 years, glutamate-induced excitotoxicity has lain at the core of theories behind the spiraling events, including mitochondrial dysfunction, oxidative stress, and protein aggregation, that lead to neurodegenerative cell death. One drug, riluzole, which possesses anti-glutamatergic properties, is approved as neuroprotective for ALS.”
I’d like to highlight that this comprehensive review related to neurotrauma in 2020 reported an “association of familial hemiplegic migraine attacks and coma with minor head trauma, mechanistically linked to calcium channel-mediated glutamate release.”
Impact of Glutamate Deficiency
Glutamate deficiency can lead to low energy, lack of concentration, memory problems, learning difficulties, mental exhaustion, and insomnia. However, glutamate deficiency is rare.
As explained by Medline Plus, there is a genetic condition known as Glutamate formimino-transferase deficiency caused by mutations in the FTCD gene.
As I mentioned in previous sections, neurodegenerative diseases, traumatic brain injury, stroke, and infections might lead to a potential deficiency and cause dysfunction.
In addition, excessive alcohol use or drug abuse is believed to increase the risk of low levels of glutamate in the brain and nervous system.
As discussed and explained in this scientific paper, it is hypothesized that excessive alcohol might inhibit the release of glutamate from nerve terminals, decrease enzyme activity, and alter glutamate receptors' function, leading to decreased signaling.
As pointed out in another scientific paper, similar to alcohol, some drugs such as opioids, methamphetamine, or cocaine might decrease the release of glutamate, block the function of glutamate receptors, and cause an increase in GABA, leading to severe imbalance.
Summary and Takeaways
As I highlighted, glutamate is critical for health and well-being in proper amounts and right times. It can improve cognitive function, mental health, and physical performance.
Excessive or deficient amounts can cause impairment of the cognitive, neural, endocrine, and immune systems leading to severe neurological and mental health disorders.
Like any other neurotransmitter or hormone, I believe this won’t be surprising, but fundamentals like a healthy diet, regular exercise, restorative sleep, rest, and fun can contribute to the balance of glutamate.
Lifestyle factors are helpful to balance, but underlying health conditions might also lead to glutamate dysfunction. Therefore seeking timely professional support is critical.
Major contributors to glutamate dysfunction are neurodegenerative diseases, traumatic brain injury, stroke, infections, genetic mutations, excessive alcohol use, and substance abuse.
Refraining from excessive alcohol use and drugs is vital for balancing glutamate and enjoying its bodily and mental functions. Increasing your hormonal intelligence can contribute to your physical and mental health.
You might also check other neurotransmitters such as dopamine, serotonin, oxytocin, GABA, acetylcholine, norepinephrine, adrenaline, and histamine that I reviewed. Glutamate interacts with all of them directly or indirectly.
Thank you for reading my perspectives. I wish you a healthy and happy life.
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