The Role of Glutamate Receptors in Epilepsy

Abstract

Glutamate is an essential excitatory neurotransmitter in the central nervous system, playing an indispensable role in neuronal development and memory formation. The dysregulation of glutamate receptors and the glutamatergic system is involved in numerous neurological and psychiatric disorders, especially epilepsy. There are two main classes of glutamate receptor, namely ionotropic and metabotropic (mGluRs) receptors. The former stimulate fast excitatory neurotransmission, are N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate; while the latter are G-protein-coupled receptors that mediate glutamatergic activity via intracellular messenger systems. Glutamate, glutamate receptors, and regulation of astrocytes are significantly involved in the pathogenesis of acute seizure and chronic epilepsy. Some glutamate receptor antagonists have been shown to be effective for the treatment of epilepsy, and research and clinical trials are ongoing.

Keywords: AMPA; NMDA; epilepsy; glutamate; kainite; metabotropic; receptor.

Figure 1

Mechanism and types of ionotropic and metabotropic glutamate receptors with associated proteins. (A) Ionotropic glutamate receptors are composed of four subunits and are structured similarly to a central ion channel pore, and are activated by NMDAR (GluN1–3 subunits), AMPAR (GluA1–4 subunits), and KAR (GluK1–5 subunits). These channels regulate Ca²⁺ permeability and play roles in receptor trafficking, synaptic plasticity, learning, memory, and even cell death. (B) Metabotropic glutamate receptors are G-protein-coupled receptors that modulate synaptic transmission and neuronal excitability. They are divided into three groups: Group I includes mGluR1 and 5; Group II includes mGluR2 and 3; Group III includes mGluR4, 6, 7, and 8. (C) Group I metabotropic receptors enhance the excitatory function in neurons. Presynaptic mGluR1 facilitates vesicular release of glutamate, and postsynaptic mGluR5 modulates the action of postsynaptic NMDARs via PSD-95 and Homer protein, leading to phosphorylation of NMDARs and potentiation of NMDAR currents. (D) Group II and Group III metabotropic receptors mainly inhibit excitatory function. mGluR2 and 3 and mGluR4, 6, 7, and 8 inhibit presynaptic glutamate release. mGluR3 is also expressed on astrocytes, positively modulating the glutamate transporter proteins GLAST and GLT-1, enhancing synaptic glutamate reuptake, and thus countering the hyperexcitability of neurons. (E) Glutamate in the synaptic cleft is taken up by astrocytes around the synapses, and is transformed to glutamine by glutamine synthetase; then, glutamine is transformed to glutamate and stored in vesicles of the presynaptic terminals to maintain neuronal communication (Figure created with BioRender.com, accessed on 23 February 2023).

Figure 2

Structures and possible mutations of ionotropic glutamate receptors with associated clinical features. (A) Ionotropic glutamate receptors such as NMDA and AMPA receptors share a common tetramer containing A–D subunits in different combinations of subunits. In NMDA receptors, the GluN1 subunit is essential for all functional NMDARs and has binding sites for glycine and D-serine. The GluN2 subunits provide glutamate-binding sites and control the expression and functional properties of NMDARs. In AMPA receptors, the GluA2 subunit is the key site for regulating calcium permeability. (B) Mutations in the subunits have been found to cause clinical syndromes. GRIN1 missense mutations can cause infantile-onset epilepsy with encephalopathies. GluN2A mutations are related to benign Rolandic epilepsy. GRIN2B gain-of-function mutation causes West syndrome. Some GRIN2D variants were reported with initial early-onset seizures. (C) The heterozygous mutations of GRIA2 gene encoding GluA2 subunit were found to have phenotypes of intellectual disability, neurodevelopmental abnormalities, and seizure (Figure created with BioRender.com, accessed on 23 February 2023).