Because of its sheer abundance throughout the central nervous system in parallel with its complicated role in several metabolic pathways, the function of glutamate as a neurotransmitter and its clinical significance has only recently been illuminated. Glutamate is now acknowledged as the principal excitatory neurotransmitter in the central nervous system. Clinically, aberrant glutamatergic activity has been associated with addiction, psychosis, neurodegeneration, and glial cell death. It has become a pharmacologic target in many areas of disease research.
Glutamate is the principal excitatory neurotransmitter of the central nervous system and the most abundant neurotransmitter in the brain. It is stored within vesicles in axon terminals and released via exocytosis upon the influx of calcium cations. It acts on both ionotropic and metabotropic receptors, including NMDA, AMPA, kainite, and G protein-linked receptors located on neurons and glial cells. The rate of its uptake from extracellular fluid largely regulates its concentration and actions in various compartments. Glutamate has clinical relevance in neurology and psychiatry, specifically regarding depression, substance use disorder, schizophrenia, neurodegenerative diseases, and other cognitive function and mood deficits.
Issues of Concern
Although essential for normative functioning, excessive glutamate activity can precipitate excitotoxicity and neurodegeneration. Agonist effects on NMDA, AMPA, kainate, and metabotropic receptors can explicate neurotoxic sequelae following cerebral ischemia, status epilepticus, and neurodegenerative diseases. Recent advances in neuroscience have revealed a genetic contribution to excitotoxic cell death diathesis and susceptibility. Of vital clinical importance are the implications of glutamatergic mediation on addiction and neurodegeneration. Chronic drug use can induce glial cell injury, which leads to glutamate dysregulation and eventually alters cortico-striatal transmission to incentivize drug-seeking behaviors. Logistically, the ubiquitous nature of glutamate makes it difficult to quantify in the body in a meaningful fashion. Despite its potential as a pharmacological target for both substance use disorders and neurodegenerative states, the glutamate pathway has historically posed problems to researchers, including serious adverse effects like increased stroke risk.
As mentioned previously, glutamate is stored within vesicles in axon terminals and released via exocytosis upon the influx of calcium cations. Once in the cleft, glutamate binds to its reciprocal receptors precipitating either ion influx (ionotropic receptors) or signal transduction cascades (metabotropic receptors), which then activate second messengers, ultimately regulating gene expression via neuroactive chemical release. Glutamate is subsequently removed from the synaptic cleft via glutamate transporters, which are present on adjacent glial cells, as well as presynaptic terminals. Once transported into the glial cell, glutamate undergoes conversion to glutamine and is transported back into the nerve terminal where it is ultimately converted back into glutamate. Glutamate connects the metabolic processes of neurons with those of astrocytes via the glutamate-glutamine cycle. Astrocytes, which account for a large proportion of brain mass and nutritional demand, act as meta compartments for up to 20% of the total glutamate in the brain. After neuronal release, glutamate accumulates in astrocytes, converted to glutamine via glutamine synthetase (an enzyme not found in neurons), phosphorylation, and ammonium (NH4). Astrocytes can also synthesize glutamate de novo and release it via exocytosis due to another enzyme not found in neurons, pyruvate carboxylase, which generates the glutamate precursor alpha-ketoglutarate. This synthesis seems to increase during brain activation, e.g., during memory formation. Neurons cannot synthesize glutamate or gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter, de novo from glucose. Instead, they hydrolyze glutamate to glutamine via mitochondrial glutaminase at glutamatergic synapses or convert it via glutamate decarboxylase to GABA.
The glutamate/GABA-glutamine cycle is a bi-directional transfer of carbon and nitrogen units, by which neurons convert glutamine precursor into glutamate and GABA neurotransmitters. Astrocytes, in turn, regenerate glutamate using glutamine and free ammonia, possibly released from neurons following their deamidation of glutamate at synapses, or synthesize glutamate de novo from glucose. The amount of de novo synthesis depends largely on the net loss of glutamate via oxidative reactions contributing to pyruvate recycling. Glutamate is metabolized through the tricarboxylic acid cycle in both neurons and astrocytes, albeit to different extents. Five high-affinity glutamate transporters are known: EAAT1 (GLAST), EAAT2 (GLT-1), EAAT3 (EAAC1), EAAT4, and EAAT5. EAAT1 and 2 are primarily responsible for glutamate uptake in the brain, coupled with three sodium ions and one hydrogen ion entering the cell, and one potassium ion leaving, which maintains a 1,000,000:1 inside-out concentration gradient.
Glutamate has all the hallmarks of a conventional neurotransmitter, plus the added complexity of the neuronal-astrocytic interplay that contributes to its recycling and to regulating excitatory brain activity. The excitatory neurotransmitter contributes to the consolidation of memories, which is the basis of long-term learning, via activation of NMDA, AMPA, and metabotropic receptors in the brain. Because of AMPA and metabotropic receptors on astrocytes, glutamate can reinforce synaptic neuronal activity (and, presumably, learning via synaptic plasticity) and recruit resting neurons into activity. In concordance with its ubiquitous presence throughout the cerebrum, it has also been implicated in neural communication, learning, and regulation.
Glutamate is a nonessential amino acid and the most abundant excitatory neurotransmitter in the human central nervous system, is the nexus between multiple metabolic pathways. It is concentrated in the synaptic vesicles of neuronal terminals, from which it is released by exocytosis, anion channels, and transporter reversal. It cannot cross the blood-brain barrier and is continuously removed from the extracellular fluid by astrocytes to prevent excessive receptor activation. Glutamate acts on several types of receptors, including excitatory amino acid transporters (EAATs 1-5), vesicular glutamate transporters (VGLUTs), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, N-Methyl-D-aspartate (NMDA) receptors, glutamine-cystine exchangers (xCT), and various intracellular carriers; one or more of these receptors are expressed on nearly every cell in the nervous system. EAATs mediate excitatory signaling, including toxicity, while AMPA and NMDA receptors have been identified as mediators of synaptic plasticity and thus learning and learned behavior. NMDA receptors are especially important, playing an instrumental role in directing cortical migration. Glutamate excitation is tightly regulated, in large part via the astrocytic/neuronal glutamate-glutamine or glutamate-GABA/glutamine cycle.
The primary methods of determining glutamate and glutamatergic receptor quantity and distribution in the body are tissue culture & fMRI. These techniques orient more toward research rather than clinical use. Logistically, the ubiquitous nature of glutamate in the body makes it difficult to test quantitatively.
Glutamate holds salience in several pathophysiological disease processes. Excitotoxicity induced by the sequential process of increased cytosolic Ca (calcium), subsequent activation of cytochrome c, and eventual apoptosis can be both acutely traumatic and chronically contributive to neurodegenerative diseases. Excitotoxicity not only incurs damages upon neurons but equally affects glial cells, as well. Furthermore, damage incurred by each glial cell type manifests distinctly. Oligodendrocytes, which are very sensitive to excess glutamate, undergo apoptosis via an AMPA receptor-mediated process similar to that of neurons. Astrocytic injury potentiates glutamate dysregulation, and microglial injury can further impair neuronal glutamate uptake and receptor expression. Precipitant disease processes manifesting from aberrant glutamatergic excitotoxicity include Alzheimer’s, multiple sclerosis, amyotrophic lateral sclerosis, and more. For these reasons, glutamate receptor expression and function, including that of GLT-1, has been identified as a potential pharmacological intervention target.
Dysfunction of NMDA receptors and resultant glutamate dysregulation also has implications in the pathophysiology of schizophrenia, but the body of research regarding this topic is less robust. Although sparse in its application, NMDA-receptor antagonists have been administered as adjuncts in the treatment of schizophrenic patients.
The pathophysiology of addiction also involves glutamate, whose homeostatic cycling becomes dysregulated with chronic drug use. Eventually, this leads to a breakdown of communication between the pre-frontal cortex and the nucleus accumbens and reinforces patterns of drug-seeking.
Outside the nervous system, glutamate may play a role in osmotic signaling that controls whole-body protein metabolism, which has important implications for skeletal muscle maintenance and cardiac function.
Excitotoxicity, for which glutamate is considered the perennial culprit, is involved in a plethora of disease processes. Glutamate’s role in synaptic plasticity has broad clinical implications, particularly regarding learning and functional disabilities, neurodegenerative diseases, and addictive behaviors. As a pathogenetic factor in substance use disorder, dysregulation in glutamate homeostasis has been shown to disrupt communication between the pre-frontal cortex and the nucleus accumbens, changing the capacity for neuroplasticity and altering dendritic spine morphology. Repeated drug use leads to an imbalance between synaptic and non-synaptic (glial) glutamate, which impairs corticostriatal control of drug-seeking behavior. This pathway also raises potential pharmacological targets; already, N-acetylcysteine has been shown to inhibit drug-seeking relapse. Excitotoxicity-induced glial injury can also mediate neurodegeneration by altering the expression of Na-dependent glutamate transporters, leaving the brain more susceptible to aberrant glutamate cycling, and contributing to diseases affecting both neurons (e.g., dementia) and glia (e.g., multiple sclerosis), alike.]