Loss of glutamate transporter eaat2a leads to aberrant neuronal excitability, recurrent epileptic seizures, and basal hypoactivity

• Published in: Glia 2022-01, Vol.70 (1), p.196-214
• Main Authors: Hotz, Adriana L., Jamali, Ahmed, Rieser, Nicolas N., Niklaus, Stephanie, Aydin, Ecem, Myren‐Svelstad, Sverre, Lalla, Laetitia, Jurisch‐Yaksi, Nathalie, Yaksi, Emre, Neuhauss, Stephan C. F.
• Format: Article
• Language: English
• Subjects: Amino acids; Animals; Astrocytes; Astrocytes - metabolism; astroglia; Brain; brain excitability; calcium imaging; Convulsions & seizures; Danio rerio; eaat2; Epilepsy; Epilepsy - metabolism; Excitability; Excitatory amino acid transporter 2; Excitatory Amino Acid Transporter 2 - genetics; Excitatory Amino Acid Transporter 2 - metabolism; Excitatory amino acid transporters; glutamate; Glutamic Acid - metabolism; Glutamic acid transporter; Larvae; Locomotion; Mutants; Neurons - metabolism; Seizures; Seizures - genetics; Seizures - metabolism; Synaptic cleft; Zebrafish; Zebrafish - metabolism
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.24106

Astroglial excitatory amino acid transporter 2 (EAAT2, GLT‐1, and SLC1A2) regulates the duration and extent of neuronal excitation by removing glutamate from the synaptic cleft. Hence, an impairment in EAAT2 function could lead to an imbalanced brain network excitability. Here, we investigated the functional alterations of neuronal and astroglial networks associated with the loss of function in the astroglia predominant eaat2a gene in zebrafish. We observed that eaat2a−/− mutant zebrafish larvae display recurrent spontaneous and light‐induced seizures in neurons and astroglia, which coincide with an abrupt increase in extracellular glutamate levels. In stark contrast to this hyperexcitability, basal neuronal and astroglial activity was surprisingly reduced in eaat2a−/− mutant animals, which manifested in decreased overall locomotion. Our results reveal an essential and mechanistic contribution of EAAT2a in balancing brain excitability, and its direct link to epileptic seizures. Main Points GRPs are progenitors present in the CNS with differentiation potential restricted to the glial lineage. These cells have been employed in the treatment of a myriad of neurodegenerative and traumatic pathologies, accompanied by promising results, herein reviewed.