Alterations in Astrocytic Regulation of Excitation and Inhibition by Stress Exposure and in Severe Psychopathology

Dysregulation of excitatory and inhibitory signaling is commonly observed in major psychiatric disorders, including schizophrenia, depression, and bipolar disorder, and is often targeted by psychological and pharmacological treatment methods. The balance of excitation and inhibition is highly sensitive to severe psychological stress, one of the strongest risk factors for psychiatric disorders. The role of astrocytes in regulating excitatory and inhibitory signaling is now widely recognized; however, the specific involvement of astrocytes in the context of psychiatric disorders with a history of significant stress exposure remains unclear. In this review, we summarize how astrocytes regulate the balance of excitation and inhibition in the context of stress exposure and severe psychopathology, with a focus on the PFC, a brain area highly implicated in psychopathology. We first focus on preclinical models to demonstrate that the duration of stress (particularly acute vs chronic stress) is key to shaping astrocyte function and downstream behavior. We then provide a hypothesis for how astrocytes are involved in stressassociated cortical signaling imbalance, discuss how this directly contributes to phenotypes of psychopathologies, and provide suggestions for future research. We highlight that astrocytes are a key target to understand and treat the dysregulation of cortical signaling associated with stress-related psychiatric disorders.