Astrocytic GABA_B1 Receptors In Mouse Hippocampus Regulate Depressive-like Behaviors

Major depressive disorder(MDD)is a very common mental disease,and its incidence has been increasing year by year.The first theory concerning the biological cause of depression revolves around monoamine neurotransmitters,which are currently the main targets for antidepressant treatment in the clinic.A variety of antidepressant drugs have been developed on the basis of the monoamine theory,such as the selective serotonin reuptake inhibitors,which have a good efficacy and safety profile.However,many limitations have been uncovered,including poor medication compliance,low efficiency of drug therapy,serious side effects and high relapse rates after medication discontinuation.Therefore,it has become an urgent issue in depression research to clarify the pathogenesis of depression and to search for novel therapeutic drug and methods.Studies have shown that mice administrated GABAB1 receptor antagonists or knockout of the GABAB1 receptors exhibited antidepressant-like behaviors.Furthermore,the expression level of BDNF mRNA in mouse hippocampus increased after administration of GABAB1 receptor antagonists in mice.And the hippocampal neurogenesis was significantly increased after knocking out the GABAB receptor in mice.Meanwhile,in the depression model of rat,the expression level of GABAB1b mRNA in hippocampus was higher than that in normal rats.These results suggest that hippocampal GABAB1 receptors may be involved in the regulation of depressive-like behaviors.However,little is known about which cell-type of GABAB1 receptors that involved in this process.Therefore,the aim of this study is to evaluate the cell-type of GABAB1 receptors in mouse hippocampal in regulating of depressive-like behaviors.Using RNA interference technology,we found that conditional knocking down of GABAB1 receptors in hippocampus in pyramidal or GABAergic neurons had no effect on the anxiety-or depressive-related behaviors.However,after conditional knocking down of GABAB1 receptors in hippocampus in astrocytes,we found a decrease in immobility time in forced swimming test(FST),which indicated that astrocytic GABAB1 receptors in hippocampus may be involved in regulating of antidepressive-like behaviors.To further validate the relationship between astrocytic GABAB1 receptors and depressive-like behaviors,we generated the astrocyte-specific GABAB1 receptors knockout mice and found a decreased immobility in FST in these mice without affecting other anxiety-and depressive-related behaviors,suggesting the role of astrocytic GABAB1 receptors in regulating of antidepressive-like behaviors.To further investigate the molecular mechanism of astrocytic GABAB1 receptors in regulating of antidepressive-like behaviors,we measured the expression level of BDNF in depressive-related brain regions from GABAB1-loxp:Aldhl-CreER(cKO)mice and control GABAB1-loxp(WT)mice.We found that the level of BDNF expressed was significantly increased in hippocampus in cKO mice.Moreover,BDNF concentrations were markedly increased in the culture medium of astrocytes isolated in hippocampus from cKO mice.However,neuronal BDNF release was undisturbed by the lack of astrocytic GABAB1 behaviors,indicating that BDNF release specifically from astrocytes was increased in cKO mice.And conditionally knock down of BDNF level in astrocytes in cKO mice restored immobility time in FST,indicating that the enhanced astrocytic BDNF in controlling antidepressive-like behaviors caused by deleting the astrocytic GABAB1 behaviors.