Mia Michaela Pal- In Cognition UK, Church Lawton, United Kingdom
This brief review article makes the argument that glutamate is deserving of its newfound attention within the neuroscience literature and that many directions of important research have yet to be explored. Glutamate is an excitatory neurotransmitter with several types of receptors found throughout the central nervous system, and its metabolism is important to maintaining optimal levels within the extracellular space. As such, it is important to memory, cognition, and mood regulation. The mechanisms by which chronic stress affect the glutamatergic system and neuroplasticity are outlined. Several implications for potential pharmacologic and non-pharmacologic interventions are discussed.
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
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References
Arnone, D., Mumuni, A. N., Jauhar, S., Condon, B., and Cavanagh, J. (2015). Indirect evidence of selective glial involvement in glutamate-based mechanisms of mood regulation in depression: meta-analysis of absolute prefrontal neuro-metabolic concentrations. Eur. Neuropsychopharmacol. 25, 1109–1117. doi: 10.1016/j.euroneuro.2015.04.016
Baker, D. A., Xi, Z. X., Shen, H., Swanson, C. J., and Kalivas, P. W. (2002). The origin and neuronal function of in vivo nonsynaptic glutamate. J. Neurosci. 22, 9134–9141. doi: 10.1523/jneurosci.22-20-09134.2002
Chitty, K. M., Lagopoulos, J., Lee, R. S., Hickie, I. B., and Hermens, D. F. (2013). A systematic review and meta-analysis of proton magnetic resonance spectroscopy and mismatch negativity in bipolar disorder. Eur. Neuropsychopharmacol. 23, 1348–1363. doi: 10.1016/j.euroneuro.2013.07.007
de Sousa, R. T., Loch, A. A., Carvalho, A. F., Brunoni, A. R., Haddad, M. R., and Henter, I. D. (2017). Genetic studies on the tripartite glutamate synapse in the pathophysiology and therapeutics of mood disorders. Neuropsychopharmacology 42, 787–800. doi: 10.1038/npp.2016.149
Fayed, N., Lopez Del Hoyo, Y., Andres, E., Serrano-Blanco, A., Bellón, J., Aguilar, K., et al. (2013). Brain changes in long-term zen meditators using proton magnetic resonance spectroscopy and diffusion tensor imaging: a controlled study. PLoS One 8:e58476. doi: 10.1371/journal.pone.0058476
Gigante, A. D., Bond, D. J., Lafer, B., Lam, R. W., Young, L. T., and Yatham, L. N. (2012). Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis. Bipolar Disord. 14, 478–487. doi: 10.1111/j.1399-5618.2012.01033.x
Guo, X., Rao, Y., Mao, R., Cui, L., and Fang, Y. (2020). Common cellular and molecular mechanisms and interactions between microglial activation and aberrant neuroplasticity in depression. Neuropharmacology 181:108336. doi: 10.1016/j.neuropharm.2020.108336
Henter, I. D., de Sousa, R. T., and Zarate, C. A. Jr. (2018). Glutamatergic modulators in depression. Harv. Rev. Psychiatry 26, 307–319. doi: 10.1097/HRP.0000000000000183
Huang, C. C., Wei, I. H., Huang, C. L., Chen, K. T., Tsai, M. H., and Tsai, P. (2013). Inhibition of glycine transporter-I as a novel mechanism for the treatment of depression. Biol. Psychiatry 74, 734–741. doi: 10.1016/j.biopsych.2013.02.020
Kantrowitz, J. T., Halberstam, B., and Gangwisch, J. (2015). Single-dose ketamine followed by daily D-Cycloserine in treatment-resistant bipolar depression. J. Clin. Psychiatry 76, 737–738. doi: 10.4088/JCP.14l09527
Maddock, R. J., Casazza, G. A., Fernandez, D. H., and Maddock, M. I. (2016). Acute modulation of cortical glutamate and GABA content by physical activity. J. Neurosci. 36, 2449–2457. doi: 10.1523/JNEUROSCI.3455-15.2016
Mandal, S., Sinha, V. K., and Goyal, N. (2019). Efficacity of ketamine therapy in the treatment of depression. Indian J. Psychiatry 61, 480–485. doi: 10.103/psychiatry.IndianJPsychiatry_484_18
Moskal, J. R., Burch, R., Burgdorf, J. S., Kroes, R. A., Stanton, P. K., Disterhoft, J. F., et al. (2014). GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists. Expert Opin. Investig. Drugs 23, 243–254. doi: 10.1517/13543784.2014.852536
Newport, D. J., Carpenter, L. L., McDonald, W. M., Potash, J. B., Tohen, M., and Nemeroff, C. B. (2015). Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am. J. Psychiatry 172, 950–966. doi: 10.1176/appi.ajp.2015.15040465
Preskorn, S., Macaluso, M., Mehra, D. O., Zammit, G., Moskal, J. R., Burch, R. M., et al. (2015). Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J. Psychiatr. Pract. 21, 140–149. doi: 10.1097/01.pra.0000462606.17725.93
Reznikov, L. R., Fadel, J. R., and Reagan, L. P. (2011). “Glutamate-mediated neuroplasticity deficits in mood disorders,” in Neuroplasticity, eds J. A. Costa e Silva, J. P. Macher, and J. P. Olié (Tarporley: Springer), 13–26. doi: 10.1007/978-1-908517-18-0_2
Sah, P., Westbrook, R. F., and Luthi, A. (2008). Fear conditioning and long-term potentiation in the amygdala: what really is the connection? Ann. N. Y. Acad. Sci. 1129, 88–95. doi: 10.1196/annals.1417.020
Singh, J. B., Fedgchin, M., Daly, E., Xi, L., Melman, C., and De Bruecker, G. (2016). Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol. Psychiatry 80, 424–431. doi: 10.1016/j.biopsych.2015.10.018
Vasilescu, A. N., Schweinfurth, N., Borgwardt, S., Gass, P., Lang, U. E., Inta, D., et al. (2017). Modulation of the activity of N-methyl-d-aspartate receptors as a novel treatment option for depression: current clinical evidence and therapeutic potential of rapastinel (GLYX-13). Neuropsychiatr. Dis. Treat. 13, 973–980. doi: 10.2147/NDT.S119004
Vivar, C., and van Praag, H. (2017). Running changes the brain: the long and the short of it. Physiology 32, 410–424. doi: 10.1152/physiol.00017.2017
Watkins, J. C., and Jane, D. E. (2006). The glutamate story. Br. J. Pharmacol. 147, 100–108. doi: 10.1038/sj.bjp.0706444
Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., and Elmer, G. I. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481–486. doi: 10.1038/nature17998
Zanos, P., Piantadosi, S. C., Wu, H. Q., Pribut, H. J., Dell, M. J., and Can, A. (2015). The prodrug 4-chlorokynurenine causes ketamine-like antidepressant effects, but not side effects, by NMDA/glycineB-site inhibition. J. Pharmacol. Exp. Ther. 355, 76–85. doi: 10.1124/jpet.115.225664
Keywords: glutamate, neuroplasticity, GABA, NMDA–receptor, long-term potentiation
Citation: Pal MM (2021) Glutamate: The Master Neurotransmitter and Its Implications in Chronic Stress and Mood Disorders. Front. Hum. Neurosci. 15:722323. doi: 10.3389/fnhum.2021.722323
Received: 08 June 2021; Accepted: 13 September 2021;
Published: 29 October 2021.
Edited by:
Arturo Ortega, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, MexicoReviewed by:
Zila Martinez-Lozada, Children’s Hospital of Philadelphia, United StatesAxel Hutt, Inria Nancy–Grand-Est Research Centre, France
Copyright © 2021 Pal. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mia Michaela Pal, Y29udGFjdEBwdXJwbGVzdGFyY29hY2hpbmcuY29t; Y29udGFjdEBpbi1jb2duaXRpb24uY28udWs=