Journal Article

The role of glutamate receptors and transporters in epilepsy: evidence from animal studies

de Barros Viana, Milena, Lemes, Jéssica Alves, Ribeiro, Alessandra Mussi, Ribeiro, Daniel Araki, Rocha, Sophia Morya Santos, Sebastião, Ana Maria, Vaz, Sandra Henriques, Bandeira, Susana Sieiro, Armada-Moreira, Adam, Rosário, Barbara dos Anjos

2025

Overview

Epilepsy encompasses a group of chronic brain disorders characterized by recurrent, hypersynchronous activity of neuronal clusters, with epileptic seizures being the primary manifestation of these disorders. The objective of epilepsy treatment is to prevent seizures with minimum adverse side effects. However, approximately 30 % of patients do not respond to available medications. One proposed mechanism of epileptogenesis is glutamate excitotoxicity. When released in excess or not appropriately removed from the synaptic cleft, glutamate hyperactivates receptors, causing a biochemical cascade, which culminates in seizures and cell death. The use of animal models is essential for uncovering potential epileptogenic pathways, understanding the role of receptors and transporters in excitotoxicity, and screening effective antiepileptic treatments. This review examines studies that investigate the role of glutamate transporters and receptors in excitotoxicity and epileptogenesis using animal models. For this, we searched through both PubMed/Medline and ScienceDirect databases. After applying the inclusion and exclusion criteria, 26 (twenty-six) studies were selected for analysis. The studies addressed key glutamate transporter family of excitatory amino acid transporters (EAATs) EAAT1, EAAT2, and EAAT3, responsible for glutamate clearance, as well as AMPA receptor subunits GluA1 and GluA2, NMDA receptor subunits GluN1, GluN2a, and GluN2b, and the metabotropic receptors mGluR5 and mGluR2/3. Results showed that the dysregulation of these transporters and receptors is associated to seizure induction and excitotoxic damage, pointing to their fundamental role in the mechanisms of excitotoxicity and epileptogenesis. These findings highlight the potential of targeting glutamate transporters and receptors to stabilize glutamate homeostasis as an intervention in epilepsy management.

• Publisher: De Gruyter,Walter de Gruyter GmbH
• Subject: Amino acids / Animal models / Animals / Cell death / Convulsions & seizures / Disease Models, Animal / Epilepsy / Epilepsy - metabolism / epileptic seizures / Excitatory amino acid transporters / Excitotoxicity / glutamate excitotoxicity / Glutamate Plasma Membrane Transport Proteins - metabolism / Glutamate receptors / glutamate transporters / Glutamic acid receptors (ionotropic) / Glutamic acid receptors (metabotropic) / Glutamic acid transporter / Homeostasis / Humans / Metabotropic receptors / N-Methyl-D-aspartic acid receptors / Receptors, Glutamate - metabolism / Seizures / Synaptic cleft / α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid / α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors