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 astrocytespecific GABABR-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.

The ATP Level in the mPFC Mediates the Antidepressant Effect of Calorie Restriction

Food deprivation can rescue obesity and overweight-induced mood disorders,and promote mood performance in normal subjects.Animal studies and clinical research have revealed the antidepressant-like effect of calorie restriction,but little is known about the mechanism of calorie restriction-induced mood modification.Previous studies have found that astrocytes modulate depressive-like behaviors.Inositol 1,4,5-trisphosphate receptor type 2(IP3R2)is the predominant isoform in mediating astrocyte Ca2+signals and its genetic knockout mice are widely used to study astrocyte function in vivo.In this study,we showed that deletion of IP3R2 blocked the antidepressant-like effect induced by calorie restriction.In vivo microdialysis experiments demonstrated that calorie restriction induced an increase in ATP level in the medial prefrontal cortex(mPFC)in naïve mice but this effect disappeared in IP3R2-knockout mice,suggesting a role of astrocytic ATP in the calorie restriction-induced antidepressant effect.Further experiments showed that systemic administration and local infusion of ATP into the mPFC induced an antidepressant effect,whereas decreasing ATP by Apyrase in the mPFC blocked calorie restriction-induced antidepressant regulation.Together,these findings support a role for astrocytic ATP in the antidepressant–like effect caused by calorie restriction.