How does glutamate function as the brain’s primary excitatory neurotransmitter. What are the implications of glutamate in chronic stress and mood disorders. How can understanding glutamate lead to new treatments for depression and anxiety.

The Rise of Glutamate in Neuroscience Research

Glutamate, once overshadowed by more well-known neurotransmitters like serotonin and norepinephrine, has recently gained significant attention in the neuroscience community. This surge in interest is due to the recognition of glutamate’s crucial role as the brain’s primary excitatory neurotransmitter and its involvement in various neurological processes.

Why has glutamate suddenly become so prominent in neuroscience literature? The answer lies in its pervasive influence on brain function and its potential implications for understanding and treating various neurological and psychiatric disorders.

Glutamate: The Brain’s Principal Excitatory Neurotransmitter

Glutamate is the most abundant free amino acid in the mammalian brain, playing a pivotal role in numerous metabolic pathways. Its significance extends far beyond mere abundance, as it serves as the primary excitatory neurotransmitter in the central nervous system (CNS).

Storage and Transmission of Glutamate

How is glutamate stored and released in the brain? Glutamate is stored in synaptic vesicles within nerve terminals. When a neuron is stimulated, these vesicles release glutamate into the extracellular space through a process called exocytosis. This release can result in high concentrations of glutamate in the synaptic cleft, the narrow space between neurons where neurotransmission occurs.

In addition to synaptic release, there is a constant low-level presence of glutamate in the extracellular space. This basal extracellular glutamate originates from non-vesicular release via the cystine-glutamate antiporter system. Maintaining optimal levels of extracellular glutamate is crucial for proper brain function, as both too little and too much can have detrimental effects on neurons.

Glutamate Receptors and Their Functions

What types of receptors respond to glutamate in the brain? Glutamate interacts with two main classes of receptors:

• Ionotropic receptors: These include NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), and kainate receptors. They mediate fast excitatory transmission in the brain.
• Metabotropic receptors: This family consists of eight subtypes (mGluR1-8) located throughout the CNS. They modulate neuronal excitability and neurotransmitter release.

The diverse array of glutamate receptors and their widespread distribution in the brain contribute to glutamate’s complex role in neurotransmission and neuroplasticity.

Glutamate’s Role in Neuroplasticity

Neuroplasticity refers to the brain’s ability to change and adapt in response to experiences. Glutamate plays a crucial role in several neuroplasticity mechanisms, including:

• Long-term potentiation (LTP)
• Regulation of dendritic spine density
• Synaptic reorganization

These processes are fundamental to learning, memory formation, and mood regulation. How does glutamate contribute to these neuroplastic changes?

Long-Term Potentiation and Memory Formation

Long-term potentiation is a process that strengthens synaptic connections, crucial for learning and memory formation. NMDA and AMPA glutamate receptors are key players in this process. When activated, these receptors trigger a cascade of events that lead to enhanced synaptic transmission, facilitating the formation and consolidation of memories.

Dendritic Spine Regulation and Mood

Dendritic spines are small protrusions on neuronal dendrites that receive synaptic inputs. Glutamate signaling plays a vital role in regulating the density and morphology of these spines. This regulation is essential for maintaining proper neuronal connectivity and is closely linked to mood regulation and cognitive function.

The Impact of Chronic Stress on Glutamate Function

While glutamate is essential for normal brain function, chronic stress can disrupt the delicate balance of the glutamate system, leading to various neurological and psychiatric issues. How does chronic stress affect glutamate signaling in different brain regions?

Hippocampus: Memory and Learning

In the hippocampus, a region crucial for memory formation, chronic stress leads to:

• Increased glutamate release
• Impaired long-term potentiation
• Atrophy of apical dendrites
• Learning and memory deficits

Prefrontal Cortex: Attention and Executive Function

The prefrontal cortex, responsible for higher-order cognitive functions, experiences the following changes under chronic stress:

• Decreased glutamate release
• Impaired long-term potentiation
• Reduced dendritic spines
• Impaired attention and executive function

Amygdala: Emotion and Anxiety

In the amygdala, a key region for emotional processing, chronic stress results in:

• Decreased glutamate release
• Impaired or enhanced long-term potentiation
• Dendritic hypertrophy
• Increased dendritic spines
• Heightened anxiety

Glutamate Dysfunction in Mood Disorders

The role of glutamate in mood disorders has become increasingly apparent through various pre-clinical and clinical studies. How is glutamate implicated in conditions such as major depressive disorder (MDD) and bipolar disorder (BD)?

Major Depressive Disorder

In patients with MDD, researchers have observed glutamate reductions in several neural areas. This finding suggests that disruptions in glutamate signaling may contribute to the development and persistence of depressive symptoms.

Bipolar Disorder

Studies investigating glutamate levels in bipolar disorder have yielded mixed results. Some research indicates alterations in glutamate signaling, but the exact nature of these changes remains unclear and may vary depending on the mood state (manic, depressive, or euthymic).

Genetic Factors

Several glutamatergic genes, affecting different types of glutamate receptors, have been implicated in mood disorders. This genetic link further supports the role of glutamate dysfunction in the etiology of these conditions.

Glutamate-Based Treatments for Mood Disorders

The recognition of glutamate’s role in mood disorders has opened up new avenues for treatment. How are researchers leveraging this knowledge to develop novel therapeutic approaches?

Ketamine and Rapid-Acting Antidepressants

One of the most promising developments in this field is the use of ketamine, an NMDA receptor antagonist, as a rapid-acting antidepressant. Unlike traditional antidepressants that can take weeks to show effects, ketamine has demonstrated the ability to alleviate depressive symptoms within hours in some patients.

How does ketamine work as an antidepressant? While the exact mechanisms are still being studied, it’s believed that ketamine’s interaction with glutamate receptors triggers a cascade of events that rapidly increase synaptic plasticity and neural connectivity, leading to improvements in mood and cognitive function.

Other Glutamatergic Agents

Beyond ketamine, researchers are investigating several other glutamatergic agents for their potential in treating mood disorders. These include:

• NMDA receptor modulators
• AMPA receptor potentiators
• Metabotropic glutamate receptor agonists and antagonists

These compounds target different aspects of the glutamate system, offering potential for more targeted and personalized treatment approaches.

Future Directions in Glutamate Research

As our understanding of glutamate’s role in brain function and mood disorders continues to grow, what are the promising areas for future research and potential therapeutic developments?

Neuroimaging and Biomarkers

Advanced neuroimaging techniques, such as magnetic resonance spectroscopy (MRS), are enabling researchers to measure glutamate levels in the living human brain. This capability opens up possibilities for identifying glutamate-related biomarkers that could aid in diagnosis and treatment selection for mood disorders.

Personalized Medicine Approaches

Given the complex interplay between glutamate and other neurotransmitter systems, future research may focus on developing personalized treatment approaches. These strategies would take into account an individual’s unique glutamate profile and genetic factors to tailor interventions for optimal efficacy.

Combination Therapies

Exploring combinations of glutamatergic agents with traditional monoamine-based antidepressants or psychotherapies may lead to more effective treatment regimens. These combination approaches could potentially address multiple aspects of mood disorders simultaneously.

Glutamate Modulation in Other Psychiatric Disorders

While much of the current research focuses on depression and bipolar disorder, the glutamate system’s involvement in other psychiatric conditions, such as anxiety disorders, schizophrenia, and substance use disorders, warrants further investigation. Understanding glutamate’s role in these conditions could lead to novel treatment strategies across a broader spectrum of mental health disorders.

In conclusion, the emergence of glutamate as a key player in neuroscience research has revolutionized our understanding of brain function and mood disorders. As we continue to unravel the complexities of glutamate signaling and its implications in mental health, we open doors to more effective, targeted treatments for millions of individuals suffering from mood disorders and other psychiatric conditions. The future of glutamate research holds promise for significant advancements in the field of psychiatry and neuroscience, potentially transforming the landscape of mental health care in the coming years.

Glutamate: The Master Neurotransmitter and Its Implications in Chronic Stress and Mood Disorders

The Sudden Popularity of Glutamate

Until recently, glutamate has often been mentioned only as a sidenote to the more well-known neurotransmitters such as serotonin and norepinephrine. Like the shy kid who suddenly became visible with a new haircut, glutamate has taken the neuroscience literature by storm. This brief review article will explain why glutamate is deserving of this newfound attention and may well be the master neurotransmitter responsible for shaping the entire brain.

Functions and Mechanisms of Glutamate

Storage and Transmission

Over the past three decades, researchers have learned that glutamate is the major excitatory neurotransmitter of the healthy mammalian brain, as the most profuse free amino acid that happens to sit at the intersection between several metabolic pathways (Watkins and Jane, 2006; Zhou and Danbolt, 2014). Glutamate is stored in synaptic vesicles of nerve terminals until it is released by exocytosis into the extracellular fluid, where it can quickly become highly concentrated (Zhou and Danbolt, 2014). Additionally, micromolar concentrations of basal extracellular glutamate, originating from non-vesicular release from the cystine-glutamate antiporter, continue to circulate in the space outside the synaptic cleft (Baker et al., 2002). Maintaining optimal levels in this space is essential, as low levels can deplete energy whereas excess levels can lead to cell death (Zhou and Danbolt, 2014). Glutamate transporters located on the outside of astrocytes and neurons quickly act to remove excess glutamate (Zhou and Danbolt, 2014). Receptor proteins at the surface of cells detect glutamate in the extracellular fluid and receive it (Zhou and Danbolt, 2014).

Most cells in the central nervous system (CNS) express at least one type of glutamate receptor. These include the ionotropic N-methyl-D-aspartate (NMDA), AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), and kainite receptors, which mediate fast excitatory transmission; in addition to the family of eight metabotropic glutamate receptors (mGluR1-8), which are located pre-, post-, and extra-syntactically throughout the CNS (Watkins and Jane, 2006; Reznikov et al. , 2011; Zhou and Danbolt, 2014). The complex and widespread mechanisms of transmission mean that there is almost unlimited potential for research on each class of receptors and sub-receptors (Watkins and Jane, 2006).

Neuroplasticity

As a neurostimulator, there is strong support for a role for glutamate in a variety of neuroplasticity mechanisms including long-term potentiation (LTP), regulation of spine density, and synaptic reorganization (Reznikov et al., 2011). As a result, glutamate is now known to be exceptionally important in cognition, learning and mood, all areas in which neuroplasticity is essential to adapting to environmental stressors (Reznikov et al., 2011). LTP in several structures of the CNS employs NMDA and AMPA glutamate receptors to strengthen synaptic connections, necessary for learning and memory (Lynch, 2004; Sah et al., 2008). Morphologic adaptation is necessary for the regulation of mood and cognition (Reznikov et al., 2011).

However, chronic stress can lead to malfunctioning of the glutamate system and reduced neuroplasticity. In the hippocampus, chronic stress leads to increased glutamate release, impaired LTP, atrophy of the apical dendrites, and learning and memory deficits (Reznikov et al., 2011). In the prefrontal cortex, chronic stress leads to decreased glutamate release, impaired LTP, reduced dendritic spines, and impaired attention (Reznikov et al., 2011). In the amygdala, chronic stress leads to decreased glutamate release, impaired or enhanced LTP, dendritic hypertrophy, increased dendritic spines, and anxiety (Reznikov et al., 2011). Guo et al. (2020) have suggested that the negative impact of stress may be due to activation of the microglial cells, which trigger neuroinflammation, affecting both intracellular and extracellular signaling pathways.

Potential for Future Treatment

Antidepressant Medications

Glutamate system dysfunction has been implicated in several pre-clinical and clinical studies of mood and disorders. Glutamate reductions have been noted in several neural areas of patients with MDD (Arnone et al. , 2015), while mixed results were found with bipolar disorder (Gigante et al., 2012; Chitty et al., 2013), and several glutamatergic genes affecting different kinds of receptors have been implicated in mood disorders (de Sousa et al., 2017). Several glutamatergic agents have been demonstrated to effectively decrease depressive symptoms in people with MDD and bipolar disorder (BD) (Henter et al., 2018).

Among the most studied is ketamine, which rapidly achieves its antidepressant effects with long-lasting effects of a small dose in even treatment resistant MDD and BD (Kantrowitz et al., 2015; Newport et al., 2015; Mandal et al., 2019). Although the mechanisms of ketamine’s actions are still not understood, preclinical studies in mice suggest that found that its antidepressant effects may be produced by the metabolite (2R,6R)-hydroxynorketamine (HNK) that increases AMPA receptor activation (Zanos et al., 2016). Intravenous esketamine, an S(+) enantiomer of ketamine with a high affinity for NMDA receptors, was found to have a rapid and robust antidepressant effect within 2 h in several large randomised controlled trials (RCT) of people with MDD (Singh et al. , 2016), and has now been approved within the United States for intranasal administration for people with high risk of suicide (Henter et al., 2018).

Two subunit NR2B-specific NMDA receptor antagonists were recently tested for MDD. While CP-101,606 (traxoprodil) was effective but was halted due to cardiovascular toxicity, MK-0657 (CERC-301) had no significant side effects but had mixed outcomes (Henter et al., 2018). Rapastinel, a glycine partial NMDA agonist, has shown high efficacy in clinical trials for major depression disorder (MDD), and has now been approved for the adjunctive treatment of MDD in the United States (Moskal et al., 2014; Preskorn et al., 2015; Vasilescu et al., 2017). Preliminary results show that sarcosine, a glycine transporter-I inhibitor that potentiates NMDA function, was more effective that citalopram, with no significant side effects (Huang et al., 2013). 4-Cl-KYN (AV-101), a highly selective glycine receptor antagonist, was highly effective in animal studies and is now being tested in clinical trials for MDD (Zanos et al. , 2015). Additionally, there are agents that target the mGluRs, but none have been demonstrated to achieve a strong anti-depressive effect (Henter et al., 2018). Thus, the mechanisms and effectiveness of several glutaminergic agents require further study.

Natural Boosts for Everyday Functioning

Another reason to get glutamate into the public eye is that with minimal knowledge of its mechanisms, there are many natural ways the lay public can boost their overall health and wellbeing. Physical exercise and mindfulness exercises have both been demonstrated to be powerful modulators of non-pharmaceutical glutamate and GABA interventions.

Physical exercise leads to increase levels of both glutamate and GABA (Maddock et al., 2016), resulting in participants feeling energized and focused while also experiencing psychological calm. In adult rats, running has been demonstrated to stimulate neurogenesis and increase the gene expression levels of the NR2B subunit of the NDMA receptor in the dentate gyrus, leading to enhanced learning, memory, and mood functioning (Vivar and van Praag, 2017). In humans, three different experiments show that vigorous physical activity results increased content of glutamate and GABA in the visual and anterior cingulate cortices in comparison with sedentary activity (Maddock et al., 2016). Levels rose approximately five percent and persisted for at least 30 min post-exercise. Additionally, participants who had higher levels of exercise in the previous week also had higher resting glutamate levels.

Mindfulness has a strong impact on brain glutamate levels observed in the brains of people who meditate mindfulness (Fayed et al., 2013). A cross-sectional study comparing the brains of meditators from a Zen Buddhist monastery with hospital staff showed a negative correlation between years of meditation and levels of glutamate in the left thalamus, which may indicate a higher level of efficiency of glutamate metabolism in this area (Fayed et al., 2013). The Zen meditators also had high myo-inositol concentrations in the posterior cingulate, which may indicate higher levels of glial and microglial activation. The exact mechanisms by which glutamate may modulate the effects of mindfulness still must be explored.

Conclusion

This brief review has highlighted the widespread impact of glutamate throughout the brain health. Glutamate is critical for maintenance of ideal energy levels, necessary for most CNS functions, and neuroplasticity, which is critical for adaptation to changes in the environment. Rather than being delegated as a sidenote as in the past, glutamate is deserving of a main focus in future neuroscience research and clinical studies. Additionally, efforts should be made to educate the lay public as to the importance of glutamate to everyday functioning and how to maintain healthy levels for increased resiliency in times of stress.

Author Contributions

The author confirms being the sole contributor of this work and has approved it for publication.

Conflict of Interest

MP is the Director at In Cognition UK, private clinic and sole author to the presented research. This research has been conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Glutamate – Disease & Food

By Lindsey KonkelMedically Reviewed by Rosalyn Carson-DeWitt, MD

Reviewed: October 17, 2015

Medically Reviewed

The neurotransmitter glutamate is produced in your body, and is also found in many foods.

Glutamate is a neurotransmitter that sends signals in the brain and throughout the nerves in the body.

Glutamate plays an important role during brain development. Normal levels of glutamate also help with learning and memory.

Having too much glutamate in the brain has been associated with neurological diseases such as Parkinson’s disease, multiple sclerosis, Alzheimer’s disease, stroke, and ALS (amyotrophic lateral sclerosis or Lou Gehrig’s disease).

Problems in making or using glutamate have also been linked to a number of mental health disorders, including autism, schizophrenia, depression, and obsessive-compulsive disorder (OCD).

Glutamate and Disease

Glutamate has many important functions in the brain, in addition to passing chemical messages from one nerve cell to another.

Too much glutamate may damage nerve cells and the brain.

There are two ways that glutamate can be damaging: There can be too much glutamate in the brain, or the receptors for glutamate on receiving nerve cells may be oversensitive, meaning that fewer glutamate molecules are needed to excite them.

At high concentrations, glutamate can overexcite nerve cells, causing them to die. Prolonged excitation is toxic to nerve cells, causing damage over time. This is known as excitotoxicity.

Researchers are studying therapies that attempt to inhibit glutamate activity for the treatment of ALS.

Glutamate and Food

Glutamate is a naturally occurring amino acid found in many different types of food. Amino acids are the building blocks of protein.

Glutamate is perhaps best known as the food additive monosodium glutamate (MSG).

MSG is used as a flavor enhancer commonly found in American-style Chinese food, canned soups and vegetables, and processed meats.

MSG can also be found naturally in many foods, including tomatoes, cheeses, mushrooms, seaweed, and soy.

While some people report adverse reactions to MSG, such as headaches, nausea, or heart palpitations, researchers have found no definitive link between MSG and these symptoms.

According to the Food and Drug Administration (FDA), MSG is generally safe at the levels commonly found in the typical American diet.

By subscribing you agree to the Terms of Use and Privacy Policy.

Editorial Sources and Fact-Checking

• Glutamate brain basics, National Institute of Mental Health
• Glutamate and food, U.S. FDA
• Glutamate and disease, The ALS Association
• Glutamate and excitotoxicity, Stanford University

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Parkinson’s disease and the glutamatergic system

Parkinson’s disease and the glutamatergic system

Website of the publishing house “Media Sfera”
contains materials intended exclusively for healthcare professionals. By closing this message, you confirm that you are a registered medical professional or student of a medical educational institution.

Mironova Yu.S.

Siberian State Medical University, Tomsk, Russia

Zhukova N.G.

Siberian State Medical University of the Ministry of Health of Russia, Tomsk, Russia

Zhukova I.A.

Department of Neurology and Neurosurgery, Siberian State Medical University of the Ministry of Health of the Russian Federation, Tomsk

Alifirova V.M.

Siberian State Medical University, Tomsk

Izhboldina O. P.

Department of Neurology and Neurosurgery, Siberian State Medical University of the Ministry of Health of the Russian Federation, Tomsk

Latypova A.V.

Siberian State Medical University, Tomsk, Russia

Parkinson’s disease and glutamatergic system

Authors:

Mironova Yu.S., Zhukova N.G., Zhukova I.A., Alifirova V.M. , Izhboldina O.P., Latypova A.V.

More about the authors

Magazine:

Journal of Neurology and Psychiatry. S.S. Korsakov.

2018;118(5): 138-142

DOI:

10.17116/jnevro201811851138

How to quote:

Mironova Yu.S., Zhukova N.G., Zhukova I.A., Alifirova V.M., Izhboldina O.P., Latypova A.V. Parkinson’s disease and the glutamatergic system. Journal of Neurology and Psychiatry. S.S. Korsakov.
2018;118(5):138-142.
Mironova YuS, Zhukova NG, Zhukova IA, Alifirova VM, Izhboldina OP, Latypova AV. Parkinson’s disease and glutamatergic system. Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova. 2018;118(5):138-142. (In Russ.)
https://doi.org/10.17116/jnevro201811851138

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Clinical variants of Parkinson’s disease (PD) are not limited to a complex of motor manifestations, but include a wide range of different non-motor symptoms: cognitive, psychotic, autonomic and sensory. Often, it is non-motor manifestations that precede the development of the classical motor picture of the disease, which has recently been actively studied in the course of neuroimaging, pathomorphological and genetic studies. Therefore, today PD is considered as a multisystem, heterogeneous disorder associated with multineurotransmitter dysfunction. This leads to the understanding that not only dopaminergic, but also other neurotransmitter systems, including glutamatergic, are involved in the pathogenesis of PD. The article deals with the participation of the glutamatergic system in the formation of the neurodegenerative process. The role of glutamate as a neurotransmitter and neurotoxin in the pathogenesis of PD and in the development of its clinical manifestations is discussed. It is assumed that the study of the state of glutamate excitotoxicity in patients with PD will improve treatment tactics and correct pathogenetic therapy.

Keywords:

Parkinson’s disease

glutamate

excitotoxicity

Authors:

Mironova Yu.S.

Siberian State Medical University, Tomsk, Russia

Zhukova N.G.

Siberian State Medical University of the Ministry of Health of Russia, Tomsk, Russia

Zhukova I.A.

Department of Neurology and Neurosurgery, Siberian State Medical University of the Ministry of Health of the Russian Federation, Tomsk

Alifirova V.M.

Siberian State Medical University, Tomsk

Izhboldina O.P.

Department of Neurology and Neurosurgery, Siberian State Medical University of the Ministry of Health of the Russian Federation, Tomsk

Latypova A.V.

Siberian State Medical University, Tomsk, Russia

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Currently, the issues of the occurrence of Parkinson’s disease (PD), the role of possible triggering factors in the development of early non-motor and basic motor disorders, as well as the causes of certain clinical variants of the course of the disease, are being actively studied. It is generally accepted that the key mechanism for the development of PD is the degeneration of dopaminergic neurons in the substantia nigra. However, in recent years, researchers have been paying more and more attention to the involvement of other neurotransmitter systems in the processes of pathogenesis and the formation of various clinical manifestations of PD [1, 2].

There are several hypotheses regarding the causes of the death of dopamine-producing neurons of the substantia nigra in PD, including genetic predisposition, oxidative stress, impaired mitochondrial respiration, the action of the neurotoxin glutamate, leading to increased activation of postsynaptic glutamate receptors, and to changes in the permeability of ion channels, excessive supply of ions Ca ²⁺ into cells, which increases the activity of intracellular proteases [3]. According to modern concepts, all of the above mechanisms can participate in the pathogenesis of neurodegeneration in PD simultaneously or sequentially potentiating each other. In this regard, PD can be considered as a multifactorial disease that manifests itself as a result of the interaction of genetic and environmental factors [4]. This interaction ultimately leads to the activation of apoptosis, but the trigger mechanism, as well as the sequence of pathogenetic factors of neurodegeneration, are still unclear [5].

In recent years, along with impaired dopaminergic neurotransmission, more and more evidence has been found of the important role of excitotoxicity in the development of PD [6, 7]. Excitotoxicity leads to damage and death of nerve cells due to the action of neurotransmitters that activate specific postsynaptic NMDA (N-methyl-D-aspartic acid) and AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors , and induction of apoptosis processes. An important role in this process is played by excitatory neurotransmitters, primarily glutamate [8].

Glutamate is one of the most common excitatory neurotransmitters in the vertebrate nervous system [9]. Glutamic acid itself was discovered and described by the German chemist K.Kh. Ritthausen in 1866 during the treatment of wheat gluten (gluten) with sulfuric acid [10]. Later, in 1908, the Japanese researcher at the Tokyo Imperial University K. Ikeda discovered brown crystals left after the evaporation of a large amount of broth formed by boiling edible kelp algae, which turned out to be glutamic acid. Subsequently, this method of mass production of a crystalline salt of glutamic acid (monosodium glutamate) was patented by him [11].

For the first time the idea of ​​the importance of glutamate, or rather its negative effect on the nervous system, was expressed by the Japanese researcher C. Hayashi in 1954. In his works, the introduction of glutamic acid into the ventricles of the brain of dogs and monkeys caused convulsions in animals. Towards the end of the 1950s, experiments were carried out in which glutamate depolarized and excited spinal cord neurons in cats. D. Lucas and J. Newhouse in 1957 [12] revealed the death of retinal neurons when mice were injected with monosodium glutamate. At 19J. Olney [13] discovered that this phenomenon is not limited to the retina, but affects all structures of the CNS, and proposed the term “glutamate excitotoxicity”. The scientist identified a correlation between the excitatory properties and neurotoxicity of glutamate, and also established the ability of glutamate antagonists to block neurotoxicity. Subsequently, these results were reproduced in a primate model using higher doses of glutamate [14]. These studies have shown that the hypothalamus and periventricular areas of the brain are particularly sensitive to glutamate. A similar neuroanatomical picture of degeneration was observed after brain hypoxia [15], which suggested a possible role of glutamate excitotoxicity in the process of ischemic neuronal death. Evidence supporting this theory was provided by S. Rothman [16], who demonstrated reduced sensitivity to hypoxia in hippocampal cell cultures using γ-D-glutamylglycine (an inotropic glutamate antagonist), a nonspecific inhibitor of the postsynaptic excitatory amino acid. Subsequent studies by M. Mattson et al. [17] showed the role of glutamate excitotoxicity in Alzheimer’s disease, PD, and other neurodegenerative diseases associated with oxidative stress and cellular energy deficiency. In their early studies, they found that the neurotransmitter glutamate, previously thought to function only in synapses, plays a key role in the regulation of dendritic development and synaptogenesis [18].

In neurons, glutamate is initially synthesized from the carbon of oxidized glucose through the formation of ketoglutarate in the reaction of the tricarboxylic acid cycle [19]. The mechanism by which glutamate exits the synaptic cleft is not fully understood. It is known that the release of glutamate from the synaptic vesicle occurs through exocytosis [20] from the cytosol through activated anion channels with the participation of mediator proteins [21]. Glutamate is released into the synaptic cleft and then enters astrocytes [22], where it is aminated by glutamine synthase to glutamine. The latter enters the presynaptic endings of glutamatergic neurons, turning into glutamate with the help of the phosphate-activated form of the glutaminase enzyme. The brain-specific transporter is localized selectively at the terminals of glutamatergic neurons and thus can regulate the replenishment of the glutamate pool in presynaptic terminals [19].]. It has been shown that any disturbance in the ability of astrocytes to maintain an optimal extracellular level of glutamate by functioning transport systems is closely associated with neurodegeneration due to excitotoxicity [23–25].

An important role as the main regulator of glutamate transport and its extracellular concentration is played by special transporters – glutamate transporters ( eng .: excitatory amino acid transporter – EAAT). Five Na 9 have been identified to date0096 + -dependent glutamate transporters, which are located on various brain cells [26]. It is known that EAAT1, 2, and 3 are found in endothelial cells and astrocytes, while EAAT3 is found in neurons. This indicates that glutamate is constantly circulating between endothelial cells, astrocytes, and neurons. The main function of EAAT1 and EAAT2 is considered to be the removal of glutamate from the synaptic cleft for the purpose of its subsequent conversion into glutamine. It turned out that their work depends on the concentration of extracellular glutamate [27]. It becomes obvious that glutamate itself and its transporters are involved both in the normal functioning of the brain and in the development of the neurodegenerative process. Thus, one of the key roles in the development of excitotoxicity in PD can be played by the dysfunction of glutamate transporters [28].

It is known that glutamate is one of the main excitatory mediators of the CNS, however, excessive activation of its receptors can lead to processes leading to neuronal death [29]. There are two subtypes of glutamate receptors, based on their role in the functioning of nerve cells. The first group includes ionotropic ones, which are structurally associated with ion channels and open only after they are activated by special ligands in such a way that the electrical activity of the neuron is caused by ion flows. The second group includes metabotropic receptors that are not associated with ion channels, which, using special signaling molecules, regulate metabolic processes in cells and control the activity of ionotropic receptors [30]. Metabotropic receptors are characterized by both post- and presynaptic localization and expression not only in neuronal but also in glial cells. These receptors are involved in the implementation of the mechanisms of memory, pain perception, anxiety states, as well as in the processes of neurodegeneration [31, 32]. To date, it is customary to distinguish 3 main subtypes of ionotropic glutamate receptors based on sensitivity to the most selective agonist: sensitive to NMDA, to AMPA and preferably responsive to kainic acid – kainate receptors.

Much attention is paid to NMDA receptors, since it is with their function that the increase in synaptic transmission between two neurons is associated, which persists for a long period of time after exposure to the synapse, excitation (long-term potentiation) in the hippocampus, the ability to perceive damaging actions through nociceptors (nociception), the formation electrical activity of the brain in the form of sharp waves or peaks that differ from background activity (epileptiform activity), as well as excitotoxic effects of glutamate [33]. The receptor is a heteromeric complex that interacts with several intracellular proteins with three different subunits: NMDAR 1 (NR1), NMDAR 2 (NR2), and NMDAR 3 (NR3) [34]. The NR1 subunit has 8 different variants generated by the process of synthesis of multiple isoforms of receptor subunits, the so-called alternative splicing, and encoded by one gene – GRIN1 ( EN : glutamate ionotropic receptor NMDA type subunit 1). It has been established that NR2 exists in 4 varieties (A, B, C and D), each of which is encoded by a separate gene, respectively GRIN2A , GRIN2B , GRIN2C , GRIN2D . The involvement of the NR2B subunit in the processes of learning and memory, as well as in the formation of chronic pain syndrome [35], has been established. At the end of the 20th century, NR3A and NR3B were discovered [36], which are currently being studied.

An important difference between NMDA glutamate receptors and other ionotropic receptors is that their channel transmits not only Na ⁺ and K ⁺ ions, but also Ca ²⁺ and is a second messenger and is able to modulate the cell response depending on external signal [37]. The highest density of NMDA receptors was found in the hippocampus, cerebral cortex, amygdala, and striatum [38]. This is probably why, under normal conditions, the activation of NMDA receptors is associated with the plasticity of CNS structures, learning and memory processes [39]. At present, a significant contribution of hyperactivation of ionotropic NMDA receptors to the process of death of dopaminergic neurons of the substantia nigra has been established. The mechanism of protection of neurons in the substantia nigra from the toxic effects of methamphetamine due to blockade of NMDA receptors has been shown [40, 41]. To date, there is evidence of the ability of glutamate in millimolar concentrations, which is in the synaptic cleft for several milliseconds, to activate NMDA receptors under physiological conditions [42, 43]. However, in pathology, these same receptors can be activated by lower, micromolar concentrations of glutamate, but for a significantly longer time [44, 45]. Hyperactivation of ionotropic glutamate receptors leads to a sharp increase in the transmembrane calcium current into the cell, followed by the release of Ca ²⁺ from intracellular depots, depolarization of the mitochondrial membrane and, as a result, a long-term increase in the amount of Ca ²⁺ in the cytoplasm. The high content of Ca ²⁺ in neurons triggers neurotoxic processes with the activation of proteolytic enzymes and the destruction of cellular structures, which ultimately leads to increased synthesis of nitric oxide, activation of lipid peroxidation and, as a result, to oxidative stress, disruption of the synthesis of neurotrophic factors, as well as to apoptosis [46, 47]. It follows from this that glutamate excitotoxicity can not only trigger but also aggravate the neurodegenerative process in PD.

The direct role of endogenous glutamate in the death of neurons in the substantia nigra has also been shown in ischemic brain damage, in which there is a significant increase in the concentration of extracellular glutamate [48, 49]. However, in addition to the process of acute (“classical”) excitotoxicity, it is customary to isolate the mechanism of the so-called slow (“metabolic”) excitotoxicity, which develops in neurodegenerative diseases [50].

The formation of neurodegenerative diseases such as PD is possible with changes in the functional state of receptors, metabolic disorders, and neuron energy deficiency [51, 52]. Normally, the defense systems of the brain are able to eliminate the neurotoxic effect of glutamate, since NMDA receptors are blocked by extracellular Mg ions ²⁺ , however, this blockade is a potential-dependent process, and this mechanism is turned off when neurons depolarize. The function of maintaining membrane polarization is mainly provided by ion pumps, in particular Na ⁺ /K ⁺ -adenosine triphosphatase (Na ⁺ /K ⁺ -ATPase) [53], and the transport of ions into and out of cells is an energy-dependent process . The delayed onset and slow progression of neurodegenerative diseases is based on a genetically determined defect in energy metabolism, which realizes its damaging effect only after activation of normal aging processes [54]. The decrease in the concentration of ATP in neurons, observed during aging, leads to a decrease in the activity of ATPase, which leads to membrane depolarization. It follows that even the natural concentration of extracellular glutamate can be toxic [55]. In studies in vitro on neuronal cultures, inhibition of oxidative phosphorylation by cyanides or inactivation of Na ⁺ /K ⁺ -ATPase by ouabain (strophanthin G, the most potent member of the cardiac glycoside group) led to the fact that low concentrations of glutamate became fatal, in both cases blockade of NMDA receptors prevented cell death [56].

To date, data obtained under experimental conditions indicate the likely involvement of glutamate excitotoxicity in neuronal degeneration of the Alzheimer’s type [57]. As confirmation, the fact that glutamate, as a fast neurotransmitter in brain structures, is actively involved in the functioning of the hippocampus and the cerebral cortex due to the regulation of learning and memory mechanisms can serve as confirmation [50, 58]. However, under certain conditions, it can also become an excitotoxin, taking a direct part in the neurodegenerative process [29].].

It is known that glutamate is considered as the predominant excitatory neurotransmitter in the basal ganglia, which are responsible for motor function, and in their pathology there is a motor deficit pathognomonic for PD [59]. Earlier studies in experimental animal models of PD revealed dysregulation of glutamatergic systems [60–62]. Striatal dopamine deficiency induced by injury to the nigrostriatal tract using 6-OHDA (6-hydroxydopamine—a toxin for selective killing of dopaminergic neurons in the brain) has also been shown to result in increased glutamate release [63].

Currently, the understanding of the role of glutamate as a neurotransmitter and neurotoxin in the pathogenesis of PD and the development of its clinical manifestations remains insufficiently elucidated. In this regard, an in-depth study of glutamate excitotoxicity is important in order to determine early diagnostic biomarkers of the pathological process in PD, as well as to search for new therapeutic approaches in the treatment of this disease, when neurodegeneration processes have affected only a limited number of cells.

The authors declare no conflict of interest.

*e-mail: [email protected]



Serum glutamate in patients with schizophrenia spectrum disorders and bipolar affective disorder | Seregin

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