Astrocytic GABA_B Receptors in Mouse Hippocampus Control Responses to Behavioral Challenges through Astrocytic BDNF

Major depressive disorder (MDD) is a common mood disorder that affects almost 20% of the global population. In addition, much evidence has implicated altered function of the gamma-aminobutyric acid (GABAergic) system in the pathophysiology of depression. Recent research has indicated that GABA_B receptors (GABA_BRs) are an emerging therapeutic target in the treatment of stress-related disorders such as MDD. However, which cell types with GABA_BRs are involved in this process is unknown. As hippocampal dysfunction is implicated in MDD, we knocked down GABA_BRs in the hippocampus and found that knocking down these receptors in astrocytes, but not in GABAergic or pyramidal neurons, caused a decrease in immobility in the forced swimming test (FST) without affecting other anxiety- and depression-related behaviors. We also generated astrocyte-specific GABA_BR-knockout mice and found decreased immobility in the FST in these mice. Furthermore, the conditional knockout of GABA_BRs in astrocytes selectively increased the levels of brain-derived neurotrophic factor protein in hippocampal astrocytes, which controlled the decrease in immobility in the FST. Taken together, our findings contribute to the current understanding of which cell types expressing GABA_BRs modulate antidepressant activity in the FST, and they may provide new insights into the pathological mechanisms and potential targets for the treatment of depression.