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 À/À 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 À/À 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.

Animal models contribute greatly to our understanding of brain development and function as well as its dysfunction in neurological diseases. Epilepsy research is a very good example of how animal models can provide us with a mechanistic understanding of the genes, molecules, and pathophysiological processes involved in disease. Over the course of the last two decades, zebrafish came in as a new player in epilepsy research, with an expanding number of laboratories using this animal to understand epilepsy and to discover new strategies for preventing seizures. Yet, zebrafish as a model offers a lot more for epilepsy research. In this viewpoint, we aim to highlight some key contributions of zebrafish to epilepsy research, and we want to emphasize the great untapped potential of this animal model for expanding these contributions. We hope that our suggestions will trigger further discussions between clinicians and researchers with a common goal to understand and cure epilepsy.

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