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. Glutamate has been implicated in kainate-mediated excitotoxicity due to increased cytosolic free Ca concentration, release of mitochondrial cytochrome c, and apoptotic cell death.[6]

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.[1][7]

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, due to their high expense and invasiveness. Logistically, the ubiquitous nature of glutamate in the body makes it difficult to test quantitatively.[4]

Glutamate is of importance in several pathophysiological disease processes. Excitotoxicity mediated by increased cytosolic Ca, cytochrome c release, and apoptosis is both acutely traumatic and chronically contributive to neurodegenerative diseases, probably through both cell death and pro-inflammatory pathology. Glial injury also contributes to these pathways. Diseases in question include Alzheimer’s, multiple sclerosis, amyotrophic lateral sclerosis, and more.[6][8] 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.[9] Dysfunction of NMDA receptors and resultant glutamate deregulation has implications in the pathophysiology of schizophrenia, but the body of research regarding this topic is less robust. However, NMDA receptor antagonists like memantine and clozapine are important pharmacological targets in the treatment of schizophrenic patients.[10]

Excitotoxicity, for which glutamate is considered the culprit, is involved in diabetic retinopathy and other health conditions. Glutamate’s role in synaptic plasticity has broad clinical implications, particularly around learning and functional disabilities, neurodegenerative diseases, and addictive behaviors.[6] 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.[9] Excitotoxicity-induced glial injury can also mediate neurodegeneration by altering 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.[2]

Glutamate contributes to neuronal damage via increased free Ca, the release of mitochondrial cytochrome c, and apoptotic cell death.[6] It affects each type of glial cell differently. 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. Besides substance use disorder and neurodegeneration, these pathways have implications for traumatic brain injuries and brain ischemia.[8] For these reasons, glutamate receptor expression and function, including that of GLT-1, has been identified as a potential pharmacological intervention target.[11] 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.[12]