Striatal Astrocytes Shape Behavioral Flexibility via Regulation of the Glutamate Transporter EAAT2

BACKGROUND: Striatal circuits must be modulated for behavioral flexibility, 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, influencing synaptic functioning and neural network activity. However, it remains unclear if EAAT2 responds to environmental cues to specifically shape action control. METHODS: To investigate the relationship between behavioral flexibility and experience-dependent regulation of EAAT2 expression in the dorsal striatum, mice were trained on an instrumental task. We manipulated EAAT2 expression using chemogenetic activation of astrocytic Gq signaling or in vivo morpholinos and determined the ability to adapt to novel environmental contingencies. RESULTS: The loss of behavioral flexibility with task overtraining is associated with the upregulation of EAAT2, which results in enhanced glutamate clearance and altered modulation of glutamatergic neurotransmission in the lateral part of the dorsal striatum. Interfering with EAAT2 upregulation in this striatal area preserves behavioral flexibility. CONCLUSIONS: Astrocytes are emerging as critical regulators of striatal functions. This work demonstrates that plasticity of EAAT2 expression in the lateral part of the dorsal striatum shapes behavior, thus providing novel mechanistic insights into how flexibility in action control is regulated. https://doi.org/10.1016/j.biopsych.2020.11.015

Automated summary

This study reveals that upregulation of EAAT2 in the lateral part of the dorsal striatum is associated with loss of behavioral flexibility, while interfering with this upregulation can preserve behavioral flexibility. Astrocytes play a critical role in regulating striatal functions and shaping behavior.