Loss of the glial glutamate transporter eaat2a leads to a combined developmental and epileptic encephalopathy in zebrafish
ABSTRACTAstroglial excitatory amino acid transporter 2 (EAAT2, GLT-1, SLC1A2) regulates the duration and extent of neuronal excitation by removing glutamate from the synaptic cleft. Human patients with altered EAAT2 function exhibit epileptic seizures, suggesting an important role for astroglial glutamate transporters in balancing neuronal excitability. To study the impact of EAAT2 function at the neural network levels, we generated eaat2a mutant 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 brain activity was surprisingly reduced in eaat2a-/- mutant animals, which manifested in decreased locomotion, neuronal and astroglial calcium signals. Our results reveal an unexpected key role of the astroglial EAAT2a in balancing brain excitability, affecting both neuronal and astroglial network activity.