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

Adriana L. Hotz,Laetitia Lalla,Ecem Aydin,Stephanie Niklaus,Nicolas N. Rieser,Nathalie Jurisch‐Yaksi,Emre Yaksi,Ahmed Jamali,Stephan C. F. Neuhauss,Sverre Myren‐Svelstad

doi:10.1002/glia.24106

Abstract

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.

Highlights

Astroglia are the most numerous glial cells within the central nervous system (CNS)
We show that glutamate transporter EAAT2a is required to balance brain excitability by regulating extracellular glutamate levels
Our results indicate that impaired EAAT2a function results in epileptic seizures and reduced basal brain activity (Figure 6)

Summary

| INTRODUCTION

Astroglia are the most numerous glial cells within the central nervous system (CNS). They do provide trophic support to neurons and play an important role in synapse formation and neurotransmission (Allen & Eroglu, 2017; Bazargani & Attwell, 2016; Clarke & Barres, 2013; Santello et al, 2019). We show that loss of EAAT2a transporter in larval zebrafish leads to increased brain excitability and recurrent spontaneous seizures, mimicking a human phenotype of patients with de novo mutations in EAAT2 (Epi4K Consortium, 2016; Guella et al, 2017). These seizures are manifested in zebrafish larvae by epileptic locomotor bursts and periods of excessive brain activity, accompanied by massively increased extracellular glutamate concentrations. Our in vivo model of impaired EAAT2a function results in a depressed yet hyperexcitable brain state, and mimics a form of developmental and epileptic encephalopathy (DEE)

| MATERIAL AND METHODS

| RESULTS

Findings

| DISCUSSION