By: Catherine Joachin
Introduction
Glutamate is the primary excitatory neurotransmitter of the mammalian brain (Barker-Haliski & White, 2015). It stimulates neurons to fire action potentials by activating ionotropic and metabotropic receptors, which promotes depolarization and the subsequent transmission of electrical signals across nerve cells (Hübel et al., 2017).
Mechanism and Function
Glutamate is a chemical messenger stored in small pockets called synaptic vesicles located at the end of each neuron (Cleveland Clinic, 2025). As an action potential (electrical signal) travels along a neuron, glutamate is released into the synaptic cleft, the gap separating neurons, through the opening of voltage-gated calcium channels (Cleveland Clinic, 2025; Chen et al., 2023). From there, glutamate molecules bind to different receptors located post-synaptically, while excess glutamate is recycled by astrocytes, a type of glial cell, via transporters to regulate glutamate metabolism and prevent abnormal neuronal excitability (glutamate-glutamine cycle) (Cleveland Clinic, 2025; Barker-Haliski & White, 2015).
By binding to receptors, glutamate allows an influx of positively charged ions (e.g., sodium and calcium ions) into the intracellular space (Hübel et al., 2017). This change in polarity, known as depolarization, enables the postsynaptic neuron to generate an action potential (Hübel et al., 2017). Glutamate-mediated depolarization promotes synaptic plasticity, an ability crucial to learning and memory (Chen et al., 2023).
Glutamate’s ability to bind to various types of receptors (i.e., ionotropic — ligand-gated ion channels — and metabotropic receptors, which modulate presynaptic glutamate release) means it is abundant and indispensable to normal brain function, as it contributes to the majority of excitatory processes (Chen et al., 2023; Cleveland Clinic, 2025). Glutamate is also responsible for producing gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter that regulates neuronal excitability (Cleveland Clinic, 2025).
Consequences of Glutamatergic Dysregulation
In order for the brain to function properly, glutamate levels need to be tightly regulated (Cleveland Clinic, 2025). Excessive concentrations of glutamate can have detrimental effects on the central nervous system, as hyperexcitability can damage neurons or cause them to die (Cleveland Clinic, 2025). This process is called excitotoxicity, and it is linked to the development and progression of epilepsy (Barker-Haliski & White, 2015).
Excitotoxicity and Epilepsy
Glutamate-induced excitotoxicity is a hallmark of various neurological conditions, including strokes, neurodegenerative diseases, and epilepsy (Nicolo, O’Brien & Kwan, 2019). Epileptic seizures are triggered by elevated concentrations of extracellular glutamate in epileptogenic regions such as the hippocampus (Nicolo, O’Brien & Kwan, 2019).
While mainstream anti-seizure medication typically interacts with inhibitory processes (e.g., GABA transmission), clinically supported treatments targeting glutamatergic signaling are showing progress in managing epileptic seizures (Barker-Haliski & White, 2015).
Conclusion
Glutamate is a chemical heavily involved in maintaining normal brain function through its role as the main excitatory neurotransmitter in the brain. It facilitates the transmission of electrical messages across nerve cells and contributes to important cognitive functions. Glutamate dysregulation plays a crucial role in the pathogenesis of epilepsy through excitotoxic damage. Fortunately, therapeutic strategies focused on regulating glutamatergic signaling hold potential as future seizure treatment options.
References
Barker-Haliski, M., & White, H. S. (2015). Glutamatergic Mechanisms Associated with Seizures and Epilepsy. Cold Spring Harbor Perspectives in Medicine, 5(8), a022863-. https://doi.org/10.1101/cshperspect.a022863
Chen, T.-S., Huang, T.-H., Lai, M.-C., & Huang, C.-W. (2023). The Role of Glutamate Receptors in Epilepsy. Biomedicines, 11(3), 783-. https://doi.org/10.3390/biomedicines11030783
Cleveland Clinic. (2025). Glutamate. Cleveland Clinic. [https://my.clevelandclinic.org/health/articles/22839-glutamate]
Hübel, N., Hosseini-Zare, M. S., Žiburkus, J., & Ullah, G. (2017). The role of glutamate in neuronal ion homeostasis: A case study of spreading depolarization. PLoS Computational Biology, 13(10), e1005804–e1005804. https://doi.org/10.1371/journal.pcbi.1005804
Nicolo, J.-P., O’Brien, T. J., & Kwan, P. (2019). Role of cerebral glutamate in post-stroke epileptogenesis. NeuroImage Clinical, 24, 102069–102069. https://doi.org/10.1016/j.nicl.2019.102069
