Glutamate Structure, Function, Physiology, and Dysfunction

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Glutamate is the primary mediator of  excitatory neurotransmission in the nervous system and as such, it took a long time for it to be recognized as a chemical transmitter in nervous tissue.[1][2] In the brain, it has an established role in the enduring changes underlying synaptic plasticity, memory and learning, cognition, and mood.[3] Due to its ubiquity, glutamate homeostasis is tightly maintained for optimal function, as excessive release leads to excitotoxicity and ultimately cell dead through apoptosis or necrosis.[2][4][5][6] Disruption in levels of the neurotransmitter have been associated with stress; neuropsychiatric disorders like depression, bipolar disorders, post-traumatic stress disorder (PTSD); and neurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).[6] Furthermore, under stressful conditions, glutamate is known to interact with other neurotransmitters such as dopamine, gamma-amino-butyric acid (GABA), norepinephrine, and steroids.[7]

Figure 1. Glutamate Chemical Structure. (Public domain image accessed on October 12, 2022)

As abundant as it is, glutamate levels are maintained at fine levels, and are tightly regulated in keeping with the myriad and sensitive functions it subserves. The concentration of glutamate in the brain cerebrospinal fluid is estimated to be 0.5-2 µmol/L and plasma glutamate levels range from 30 to 100 µmol/L. During synaptic transmission the glutamate concentration in the synaptic cleft fluctuates from resting levels of 0.6 µmol/L and reaches 2-1000 µmol/L, whereas the synaptic vesicles concentrate many orders of magnitude higher levels, at 100 mmol/L.[8][9]

Gutamate, is a free amino acid involved in many metabolic functions and the anion of glutamic acid functions as the chemical messenger in the nervous system (Figure 1). 40% of neurons in the central nervous system (CNS) are considered to be glutamatergic with its receptors located on 90% of neurons. Glutamate containing neurons originate mostly from the cortex and project to other cortical areas, striatum, nucleus accumbens, thalamus, cerebellum, hippocampus with  further projections from some regions to subcortical structures.

The excitatory effects of glutamate are mediated through activation of ionotropic NMDA, AMPA, and Kainate receptors, and metabotropic glutamate receptors.[10] Glutamate also serves as a source of extra-synaptic signaling when it escapes the synaptic space i.e., 'glutamate spillover', and engages in volume transmission to modulate brain function.[11]

Synthesis of Glutamate[edit]

Glutamate does not cross the blood-brain barrier and is synthesized in neurons from precursors glutamine and α-ketoglutarate. The precursor α-ketoglutarate,  an intermediate in the  tricarboxylic acid cycle (TCA) (also referred to as the Kreb’s cycle), is transaminated to glutamate by mitochondrial glutamate dehydrogenase. However, the bulk of glutamate in neurons is predominantly derived from the catalytic conversion of glutamine to glutamate by the enzyme glutaminase.[12][13]

Glutamate is released from the presynaptic terminals into the extracellular space and binds to post- and extra-synaptic receptors. Considering there are no degradative enzymes to metabolize and clear glutamate, majority of the transmitter is taken up by specific transporters into astroglial cells and neurons. In this glutamate-glutamine-glutamate cycle, glutamate is metabolized to glutamine in the glial cells by glutamine synthetase and is released for uptake by presynaptic neuron terminals. The glutamine is deamidated to glutamate in neurons via a reaction catalyzed by mitochondrial phosphate-activated glutaminase (PAG) that generates ammonia as a byproduct.[14] The glutamate-glutamine cycle accounts for more than 60% of glutamate turnover.[15]

Another source of glutamate is glucose, which is metabolized by neurons and involves the transamination of the Krebs cycle intermediate, 2-oxo glutarate.[16] However, astrocytes are the prime contributor of glutamate sourced from glucose, as the intermediates generated in the Krebs cycle that serve as a precursor of glutamine require the pyruvate decarboxylase, an enzyme present exclusively in the astrocytes.[17] The glutamine is then released to be converted to glutamate in neurons.

The de novo synthesis of glutamine in astrocytes helps maintain a pool of ideal levels of glutamate necessary for optimal neurotransmission. This process is essential as the glutamine-glutamate cycle is an open cycle and its intermediates are accessible to other metabolic pathways.[14]

Glutamate Receptors & Transporters[edit]

Glutamate Receptors[edit]

Glutamate receptors are categorized into ligand-gated ionotropic receptors and G-protein coupled metabotropic receptors.[10]

Ionotropic Glutamate Receptors[edit]

The ionotropic glutamate receptors are classified, based on their sensitivity to pharmacologic agents into NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), and Kainate receptors.[18] These tetrameric cation channels induce depolarizations in post-synaptic neurons in response to glutamate, and play a crucial role in modulating cellular excitability, synaptic plasticity, and memory and learning.

All the glutamate-gated receptors subtypes are nonspecific ion channels, allowing the passage of monovalent cations Na+ and K+, with high Ca2+ conductivity in the case of NMDA receptors. Each subunit of the receptor has an extracellular amino terminal and ligand binding site, with 3 transmembrane domains (M1, M3, M4), a reentrant p-loop (M2) that lines the channel, and an intracellular carboxy-terminal domain (CTD). The AMPA receptors (GluR1-4) mediate fast, transient synaptic transmission in the order of < 10 ms, whereas the NMDA (NR1-3) and Kainate (GluR5-7, KA1-2) receptors transduce signals at a slower rate between 10-100 ms.[18][19]

Figure 2. Crystallographic representation of the NMDA receptor, with the individual subunits colored differently. (Public domain image accessed on October 14, 2022)

The NMDA receptor (Figure 2), is an heteromer of dimers of two obligatory NR1 subunits and two NR2A-D, or NR3A-B subunits.[20][21] The isoforms of the receptor comprising the 4 subunits form the ion channel with differing properties contingent on the subunits.[10][18] NMDA receptors have unique features that are responsible for their slow activation-deactivation kinetics in response to glutamate. The receptor is extremely voltage dependent, and under negative, resting membrane conditions has a conditional Mg2+ block. This impediment is removed with more positive depolarizing potentials, thus freeing the channel for passage of other ions.[22][23]

Moreover, the NMDA receptor activation requires the binding of glutamate to the NR2 subunits and of coagonist, glycine or D-serine, to the NR1 subunit, highlighting another unique feature.[22] These properties of the receptor prevent its activation during brief and baseline synaptic pulses—keeping the brakes on Ca2+ influx. The entry of calcium upon activation initiates multiple downstream actions that reinforce and strengthen the connection between the pre- and post-synaptic neurons. The subsequent, downstream effects of Ca2+ encompass phosphorylation cascades, gene transcription, modulation and formation of dendritic spines to name a few. The cytoplasmic CTD of NMDA receptor subunits are key sites for synapse-associated protein interactions, such as with scaffolding proteins, and it also contain motifs for enzymes essential for sustaining downstream signal transduction.[24][25]  Individual splice variants of these subunits formed by alternative splicing confer different phenotypic and pharmacological properties that further impact NMDA receptor function. [21]        

The NMDA receptor has a major role in synaptic plasticity, the stable and labile alterations in neural circuits that are activated during an experience and that persist and underpin the formation of memory and support learning. [26] The receptor is considered a Hebbian-like coincidence detector of the simultaneous release of glutamate from the presynaptic neuron terminals and the activation kinetics of post-synaptic neurons—where AMPA and NMDA receptors mediate fast and slow components of excitatory post-synaptic potentials (EPSPs), respectively.[27] The neurotransmitter binds to both NMDA and colocalized AMPA receptors at post-synaptic sites and sufficient depolarization of AMPA receptor mediated EPSPs is necessary to expel the Mg2+ from, and activate NMDA receptor channels. The frequency of pulses and volume of glutamate released is higher at more active synapses and influences post-synaptic NMDA receptor function.[23]  The subsequent entry of Ca2+ into the neuron through the channel sets of a signaling cascade, including calcium-calmodulin Kinase II (CaMKII)—that alters the strength of the synapse, encoding its activity. This alteration in the robustness of synaptic connections underlie activity-dependent synaptic plasticity. The ability of the NMDA receptor to detect coincident pre- and post-synaptic signals forms the basis of long-term potentiation (LTP)—a mechanism that serves to facilitate neurotransmission and presents a model system for memory formation.[28] NMDA receptors are also linked with another closely related form of plasticity, referred to as long-term depression (LTD). The reduced efficacy of the synapse as a consequence of LTD is also know to underlie various forms of learning and memory.[29][30]

The activity associated with NMDA receptors is essentially paradoxical, and the ‘NMDA paradox’ posits that NMDA receptors are essentially protective and crucial for neuronal survival and health, whereas on the other hand they are central to neurotoxicity![31] The NMDA receptors are localized largely at synaptic sites in the mature cortex and hippocampus and there are pools of receptors that exist at peri- and extra-synaptic sites.[32][33] The main distribution pattern suggests localization of non-synaptic receptors to the dendritic shaft, neck of the dendritic spine, and cell bodies at sites away from the primary synapse, with peri-synaptic receptors as their name suggests at sites closer, ~100nm from the main synapse containing the post-synaptic density (PSD) machinery. This divergent distribution pattern of the synaptic and and extra-synaptic receptors could underpin the paradox referred to above. The synaptic NMDA receptor is crucial for ensuring the viability and resiliency of the neuron, including deploying pro-health gene expression.[32] These principal synaptic signals maintain mitochondrial integrity, bolster cellular antioxidant defenses, and curtail anti-apoptotic events, while engaging in pro-survival processes. The extra-synaptic receptor activity is the very opposite of the robust synaptic receptors and leaves the neuron vulnerable to insults.

The classic synaptic NMDA receptors respond to the trans-synaptic release of glutamate at lower frequencies and concentrations, whereas the extra-synaptic receptors are more responsive to higher and more sustained levels of glutamate and subserves more of the toxic elements of glutamate and calcium signaling. Elevated glutamate as a consequence of 'spillover' from neurons or astrocytes is also observed under conditions of traumatic brain injury, ischemia, and neurodegenerative diseases.[4][5] The selective activation of extra-synaptic receptors under these conditions manipulates pro-apoptotic and anti-survival programs all the way from the cell surface to nuclear gene expression. The response to these extra-synaptic receptors is believed to underpin the neuronal damage under conditions that incur increased glutamate.

Metabotropic Glutamate Receptors[edit]

Metabotropic glutamate receptors (mGluRs), mGluR1- mGluR8, belong to the family C G protein-coupled receptors with extensive distribution throughout the nervous system.[34] These receptors have the typical 7 transmembrane domains of G-protein coupled receptors, but differ in that they have a distinctive, large extracellular N-terminal ligand binding domain, called the Venus flytrap domain (VFD). The mGluRs based on sequence homology, G-protein coupling, and signal transduction, are grouped into 3 subfamilies, I, II, III, [34][35]

The mGluR I family couples to Gαq/11, and via the activation of phospholipase C, PLCß, mobilizes intracellular Ca2+, protein kinase C (PKC), and additionally stimulates adenylyl cyclase leading to protein kinase A (PKA) activation.[36] The mGluR I receptors are post-synaptic and are expressed by neurons and astrocytes in the nervous system and mediate fast-synaptic transmission.[35] The mGluR II and III are Gi/o coupled, and their signaling mechanisms inhibit adenylyl cyclase and furthermore they regulate various ion channels, including calcium and potassium channels. They are present in neurons and astrocytes at pre- and post-synaptic sites. The GluR6 receptor is found on post-synaptic retinal ON bipolar cells and serves to stimulate cGMP. Apart from these signaling partners these subfamilies connect with other pathways, various kinase pathways, such as mitogen-activated protein kinase (MAPK). The variety of signaling through mGluRs adds complexity to glutamatergic neurotransmission and contributes to neuronal excitability and synaptic plasticity.

Complexity  of Glutamate receptors[edit]

To further add to the complexity of glutamate signaling, multiple splice variants of these receptors generated by alternative splicing have been observed with distinct and overlapping expression patterns. Additionally, diverse combinations of heteromers within subfamilies of receptors contribute to the richness of glutamate transmissions.[18][37] Post-transnational modifications at key sites of the intracellular C-terminal domains have been demonstrated to affect receptor signaling.[18][35] The cytoplasmic CTD features motifs for protein and enzyme interactions and are crucial elements of downstream signaling.[24][25]

Glutamate Transporters[edit]

Glutamate is the primary excitatory neurotransmitter in the brain and elevated levels interfere with efficient signaling. Dysfunction related to increased glutamate can result in neurotoxicity that is executed predominantly by downstream mechanisms linked to heightened calcium. The swift removal of glutamate from the synaptic cleft is essential for effective coordination of the spatiotemporal aspects of neurotransmission. The high-affinity presynaptic transporters on neurons and glial cells work in concert to clear glutamate, terminating its action at post- and extra-synaptic sites.[38] The uptake of glutamate by astroglia cycles the neurotransmitter into the above referenced glutamate-glutamine-glutamate metabolic pathway, ensuring availability of adequate levels for neurotransmission and maintenance of glutamate homeostasis. There are 5 excitatory amino acid transporters (EAATs), EAAT1 (Glast1), EAAT2 (Glt1), EAAT3 (EAAC1), EAAT4, and EAAT5.[2][38][39] These high-affinity transporters are coupled to the ion fluxes across the membrane, namely the co-transport of 3 Na+, and 1 H+ with 1 glutamate molecule, followed by the exchanged of 1 K+ ion.[39][40]

The EAAT’s have diverse expression patterns in the mammalian brain and in neurons and glial cells. The predominantly glial EAAT2 accounts for majority, ~ 90% of glutamate uptake in the forebrain and other brain regions enriched with glutamate, and its presence is crucial for glutamate homeostasis.[41] EAAT3-EAAT5 are expressed in neurons. It is now recognized that different levels of most transporters are expressed by neurons and glia in different brain regions.

In addition, a glutamate-cysteine exchanger, xCT, transports intracellular glutamate out for cysteine into the cell. Glioma’s have been shown to have higher levels of xCT compared to EAAT’s, suggesting increased extracellular glutamate and neurotoxicity in these tumors.[42]

Glutamate Disorders[edit]

Glutamate dysfunction has been implicated in the development of numerous psychiatric disorders, such as major depressive disorder (MDD), post-traumatic stress disorder (PTSD), bipolar disorder (BP), schizophrenia; and neurodegenerative diseases including Alzheimer’s, Parkinson’s, Huntington diseases, and amyotrophic lateral sclerosis (ALS). Glutamate is also responsible for the neurotoxic effects of brain insults like ischemic stroke and traumatic brain injury (TBI). For this reason, many clinical trials aim to dissect the role of glutamate to delineate the mechanism of its actions and develop new therapeutic approaches aimed at this system. Some of the these dysfunctions are elaborated on here.

Affective Disorders[edit]

Mood disorders[edit]

Major depression disorder (MDD) and anxiety affects millions worldwide and the prevalence of these disorders has spiked during Covid 19, substantially increasing the already high burden![43] The challenging remission rates and delayed therapeutic benefit with current monoamine-targeted antidepressants like selective serotonin reuptake inhibitors (SSRIs) has focused attention on the need for alternatives, including on glutamatergic agents. Only one third of patients with MDD have been reported to achieve remission following a standard 14-week treatment of antidepressants and approximately half experience remission with two treatment cycles.[44] This highlights the refractive response to available treatments targeting the monoaminergic pathways and the challenges in deciphering the pathophysiology of these affective disorders. Depression is characterized as a mood disorder with patients experiencing persistent and low energy, loss of interest in pleasurable activities, sadness, and suicidal ideation. The reward pathway of the brain which is compromised in depression encompasses the regions involving glutamate signaling—areas that have been shown to be atrophied in depressed patients.[45] Imaging and post-mortem studies have revealed a loss of neurons and glia with a reduction in the volume of the prefrontal cortex, important for executive functions; the hippocampus important for memory, learning, and emotions; amygdala, the focal region for fear response; and the nucleus accumbens and ventral tegmental area for motivation, pleasure and reward. Deficiencies associated with these areas are prevalent in depressed patients and those with other mood disorders such as anxiety.

Glutamatergic dysfunction has broad implications for the etiology and persistence of depression and many studies corroborate its role in mood disorders. A clinical trial undertaken to  study patients with endogenous and neurotic depression, and schizoaffective disorder found increased serum glutamate levels in depressed patients on antidepressants.[46] Furthermore, patients with depression and bipolar disorders have higher levels of glutamate in the frontal cortex.[47] Plasma and platelet amino acid concentrations are also reported to be higher in depressed patients, with significantly elevated plasma levels of glutamate along with serine, taurine, and lysine.[48] Clinical studies of ketamine, an NMDA receptor antagonist and other partial antagonists like D-cycloserine have demonstrated encouraging results for symptom improvement in depressed individuals.[49]

Finally there is support from animal studies for a role of glutamate in mood disorders, for instance in anxiety inducing conditions, stress and acute administration of  NMDA receptor antagonists preferentially increased striatal and prefrontal cortical glutamate levels.[50]

Current research and clinical trials are ongoing to illuminate the role of glutamate in mood disorders and to offer therapies for treatment.

Neuropsychiatric Diseases[edit]


Dopamine dysregulation has long been central to our understanding of the pathophysiology of schizophrenia. Considering the inefficiency of dopaminergic antagonists in sufficiently and successfully alleviating the symptoms of this disorder—positive, negative, and cognitive—the focus has shifted on other neurochemical systems, including on glutamate. The evidence that NMDA receptor antagonists induce psychotic symptoms in humans and other primates has generated a significant amount of interest and research on glutamate in the etiology of schizophrenia.[51][52][53][54][55] In particular dissociative anesthetics like phencyclidine (PCP) and ketamine that block the NMDA receptor give rise to the schizophrenia-like positive and negative symptoms as well as cognitive difficulties.[51]

There has been a great deal of research on the role that glutamate plays in schizophrenia. A recent MRI study examining the dysfunction of the glutamatergic system in the pathogenesis of schizophrenia expanded on previous imaging and post-mortem studies. They wanted to specifically focus on the changes in the brain associated with the pre-symptomatic stage of schizophrenia—preceding the onset of the first psychotic episode. The study centered on a circumscribed region of the anterior hippocampus, ostensibly to serve as a diagnostic marker at the incipient phase of schizophrenia. They found a reduction in hippocampal volume in clinically high-risk individuals, concordant with the first psychotic episode. Specifically, they noted increased cerebral blood volume and hypermetabolism in the left CA1 subfield of medically naïve individuals that preceded the first psychotic episode, and that could underlie the resultant reduction in size and volume of the CA1 and subiculum.[51] Additionally, in mice models, the increase in glutamate evoked by NMDA receptor antagonists, could conceivably be responsible for the above referred to alterations, as these changes were reversed by agents that inhibit the release of glutamate. These agents include GABA receptor agonists, like gabapentin.[56]

Deficits in motor and cognitive abilities related to NMDA antagonist ketamine, evoked increases in glutamate in the prefrontal cortex, and can be attributed to non-NMDA AMPA receptor, as antagonists of these receptors restore normal function.[57] Additionally, agonists targeting metabotropic GluR 2/3 pre- and extra-synaptic receptors reduce glutamate release, ameliorating the symptoms alluded to it, and are proving to be attractive sites of intervention.[58] Thus heightened glutamate acting via AMPA receptors in the prefrontal cortex could, account for some of the psychotic and cognitive deficiencies of schizophrenia. These kinds of investigations strongly suggest the involvement of glutamate in the pathophysiology of schizophrenia.

GABAergic interneurons in the hippocampus and prefrontal cortex may be the mechanism serving as the mediator of NMDA receptor antagonist induced glutamate release. The activity of pyramidal neurons of the prefrontal cortex and hippocampus is finely tuned and stabilized by the inhibitory input from GABAergic interneurons. These interneurons have NMDA receptors that when blockaded could alleviate or lessen their inhibition of pyramidal neurons, disinhibiting them, and destabilizing the system and its ensuing response to heightened levels of glutamate.[58]

These data find support from non-human primate studies showing NMDA receptor antagonists trigger various acute effects of schizophrenia such as deficits in pulse inhibition, hyperactivity, impaired working memory, and prolongation of latent inhibition.[54][55] Recent studies have shown that the administration of NMDA receptor antagonists results in sustained changes in cognitive performance and dopamine in the frontal lobes of these animals.[59][60]

The identification of the mechanisms that underlie the glutamatergic dysfunction associated with schizophrenia could offer alternative therapeutic options for the disease. Although dopaminergic agents to treat schizophrenia have value and have traditionally been used, they leave a lot of patients with persistent symptoms and poor quality of life. Glutamate agents that could arguably make a difference in improving symptoms, should be considered equally valuable.  

Post-Traumatic Stress Syndrome (PTSD)[edit]

Stress subjects the brain to diverse levels of architectural and functional changes ranging from regional declines in volume to dendritic shaft and spine modifications.[61][62] Stress can culminate in and worsen neuropsychiatric disorders as is the case with post-traumatic stress syndrome that follows a traumatic experience.[61][62] Current approved modes for treatment of PTSD employ selective serotonin reuptake inhibitors (SSRI's) and cognitive behavioral therapy (CBT), although with varying rates of success. In light of this, it is deemed necessary to identify alternative targets to meet these unmet needs.

The NMDA receptors express different proportions of NR2A and NR2B subunits in the adult forebrain brain. These subunits are instrumental, in that they underlie synaptic plasticity which is considered crucial for fear memory formation and learning, especially in areas of the medial prefrontal cortex (mPFC) and amygdala. The receptor comprised of NR2A is concerned with the initial formation and stabilization of memories related to fear.[63] The NR2B containing receptor in the medial prefrontal cortex and amygdala modulates synaptic plasticity and is vital for fear extinction.[63] The advent of fast-acting anti-depressants such as NMDA receptor antagonist ketamine, have been known to be effective in treating PTSD, albeit with psychotomimetic side effects. Newer drug formulations, sans this side effect profile, and specifically targeting the NMDA receptor are being successfully tested for their efficacy in obtaining significant relief from PTSD symptoms, and crucially the extinction of learned fear.[64]

An ongoing clinical study of a novel allosteric modulator of the NMDA receptor that acts as a coligand with glutamate to open the receptor channel, without the required co-binding of glycine, resulted in consequential symptom improvement.[64] NYX-783 had shown in PTSD models to impair the spontaneous recovery of learned fear post-therapy—a devastating return of a condition for PTSD sufferers that relive traumatic and fear-laden memories. The mechanism of this drug's favorable action on maintainance of fear extinction centered on the NR2B-subunit containing NMDA receptors of the infralimbic mPFC.[64]

D-cycloserine, (DCS), a partial agonist of the NMDA receptor has been used as an adjunct therapy in conjunction with standard psychotherapy in the treatment of PTSD.[65] DCS enhances the fear extinction outcome, importantly when used alongside psychotherapy.[65][66][67] The improvement with DCS as it relates to fear extinction is further augmented by the simultaneous use of hydrocortisone.[68]

Further investigations and clinical trial with agents aimed at the NMDA receptor are underway to facilitate the relief of PTSD.

Neurodegenerative Diseases[edit]

Alzheimer's Disease[edit]

Similar to schizophrenia, the cortical glutamatergic system has a role in the pathology of Alzheimer's disease (AD). Memory loss and behavioral, personality changes are hallmarks of the disease and are accompanied by progressive structural, functional, and physiological changes in key regions of the hippocampus and neocortex, areas that underlie these very functions. The degeneration of these brain regions and loss of synaptic integrity can be tied to calcium mediated neurotoxicity. Elevated calcium signaling cascades lead to impaired synaptic transmission and deterioration of neuronal function that ultimately proves fatal.[5] Neurotransmission and synaptic plasticity mediated by NMDA receptors are crucial for memory acquisition and learning and have been implicated in the etiology of AD, especially due to their preferential permeability to calcium. NMDA receptor antagonists could protect neurons from this calcium toxicity and prompt symptom relief. Memantine is an uncompetitive NMDA receptor antagonist that has shown to slow excitotoxic neurodegeneration. This compound has a good safety and efficacy profile in slowing the progression of Alzheimer's disease.[69][70] Memantine works by obstructing calcium entry through activated extra-synaptic NMDA receptors at a distance from the synaptic cleft, blocking their neurotoxic effects, while largely sparing the synaptic receptors involved in normal neurotransmission and function.[33] This distinction in targeting extra-synaptic receptors that mediate neurotoxicity allows memantine to be effective in ameliorating AD symptoms.  

Recent evidence on the molecular level links ß-amyloid and tau—pathological markers of AD—to facilitating the excessive calcium influx via the NMDA receptors.[71] 

There is much ongoing research and clinical trials to discover safe and efficacious drugs that target the glutamatergic system and have a meaningful impact on modifying and delaying AD progression.

Neurotoxicity, Ischemia, and Traumatic Brain Injury[edit]

The 2019 Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) established stroke to be the second-leading cause of death globally and the third-leading cause of disability. In 2019 itself there were 12.2 million strokes and 6.55 million stroke-related deaths.[72] The WHO estimates that rates of stroke could rise further and dramatically by 2030, especially in low-income countries.[73] 

Glutamate toxicity is a consequence of numerous pathologies, brain trauma, ischemia, and has been recognized as the conclusive series of insidious events that further exacerbate the insult of these conditions.[5][74][75] Extracellular glutamate levels are tightly regulated and transporters on both neurons and glia rapidly clear up excess synaptic glutamate to maintain homeostasis.

Following an ischemic stroke, blood supply to the brain which is rich in glucose and oxygen is disrupted. The brain is deprived of its essential energy source and the immediate repercussion of this loss is diminished oxidative phosphorylation and depletion of ATP. The electrochemical gradients of intra- and extra-cellular ions required for healthy neuronal function is actively maintained by the ATP-dependent pumps that cease to function normally in this environment. Subsequently, the cells become perpetually depolarized due to Na+ influx and K+ efflux, leading to Ca2+ entry through activated calcium channels that triggers glutamate release from the cell. NMDA receptors are the primary source of glutamate mediated excitotoxicity.[75][76][77] The inordinate amount of extracellular glutamate engenders excessive excitement of glutamate receptors and prompts the further influx of Ca2+ into the cells. The elevated calcium initiates downstream cascades enlisting kinases and proteolytic enzymes that ultimately leads to mitochondrial dysfunction, generation of harmful reactive species, membrane disintegration, instigation of necrotic or apoptotic pathways, resulting finally in cell death.    

An older study assessed the duration of glutamate release following the onset of symptoms of acute ischemic stroke in order to gauge the timing of a therapeutic window for glutamate targets. Glutamate concentrations in the cerebrospinal fluid were found to be lower in patients with stable ischemic stroke during the initial 6 hours prior to returning to normal levels. This was in contrast to glutamate levels being significantly higher in patients with progressive ischemic stroke during the first 24 hours. This provides a wider duration for intervention to treat patients with ischemic stroke, treatments that include glutamate antagonists or other means of controlling the glutamate levels to stem the damaging effects of neurotoxicity.[78] Serum glutamate levels have been shown to remain elevated 15 days after ischemia, with high levels on third day being a negative indicator of neurological improvement through day 15.[79] Glutamate has been implicated in the pathogenenis of epileptic seizures following a stoke. A clinical trial underway is testing the potential of a low-glutamate diet in an attempt to treat epilepsy in a pediatric population. Lowering the consumption of free glutamate for a month would optimize micronutrient intake in these child subjects. These clinical trials are still ongoing and are expected to be completed in 2022.[80]


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