Plasticity of the glutamate transporter EAAT2 on striatal astrocytes regulates flexibility in behavior

Modulation of striatal circuits is necessary for behavioral flexibility and confers the ability to adapt to environmental changes. Striatal astrocytes contribute to circuit neuromodulation by controlling the activity of ambient neurotransmitters. In particular, extracellular glutamate levels are tightly controlled by the astrocytic glutamate transporter EAAT2, thereby influencing synaptic functioning and neural network activity. While disturbances in EAAT2 have been related to neurological dysfunctions, it remains unclear if environmental cues influence this protein9s function to specifically shape action control. In this study, we investigate the relationship between experience-dependent plasticity of EAAT2 expression and action inflexibility that follows overtraining for an instrumental task. We find that task overtraining is associated with the upregulation of EAAT2 in the lateral part of the dorsal striatum (DLS). Interfering with EAAT2 upregulation by chemogenetic activation of astrocytic Gq signaling or by transient in vivo knockdown of EAAT2 in the DLS restores behavioral flexibility. Astrocytes are emerging as critical regulators of striatal functions, and by demonstrating that plasticity of EAAT2 expression in the DLS shapes behavior, this work provides novel mechanistic insights into how flexibility in action control is regulated.