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.

Expression Patterns of Inducible Cre Recombinase Driven by Differential Astrocyte-Specific Promoters in Transgenic Mouse Lines

Astrocytes are the most abundant cell type in the central nervous system(CNS).They provide trophic support for neurons,modulate synaptic transmission and plasticity,and contribute to neuronal dysfunction.Many transgenic mouse lines have been generated to obtain astrocyte-specific expression of inducible Cre recombinase for functional studies;however,the expression patterns of inducible Cre recombinase in these lines have not been systematically characterized.We generated a new astrocyte-specific Aldh1 l1-CreER^(T2)knock-in mouse line and compared the expression pattern of Cre recombinase between this and five widely-used transgenic lines(hGfap-CreER^(T2)from The Jackson Laboratory and The Mutant Mouse Resource and Research Center,Glast-CreER^(T2),Cx30-CreER^(T2),and Fgfr3-iCreER^(T2))by crossing with Ai14 mice,which express tdTomato fluorescence following Cre-mediated recombination.In adult Aldh1 l1-CreER^(T2):Ai 14 transgenic mice,tdTomato was detected throughout the CNS,and five novel morphologicallydefined types of astrocyte were described.Among the six evaluated lines,the specificity of Cre-mediated recombination was highest when driven by Aldh1 l1 and lowest when driven by hGfap;in the latter mice,co-staining between tdTomato and NeuN was observed in the hippocampus and cortex.Notably,evident leakage was noted in Fgfr3-iCreER^(T2)mice,and the expression level of tdTomato was low in the thalamus when Cre recombinase expression was driven by Glast and in the capsular part of the central amygdaloid nucleus when driven by Cx30.Furthermore,tdTomato was clearly expressed in peripheral organs in four of the lines.Our results emphasize that the astrocyte-specific CreER^(T2)transgenic lines used in functional studies should be carefully selected.