Effect And Mechanism Of Membrane GABA_BR In The Hippocampus And Nucleus Accumbens Brain Area On Depression

Background and objective:The fatality rate of depression,after cancer,will be the second largest disease,causing human death and disability.Patients with depression can develop psychotic symptoms,lasting for a long time and repeated attacks,seriously affecting the normal life of patients,now there is still no exact way to regulate depression.Therefore,it is of great significance to further clarify the mechanism of the development of depression,seek more reasonable treatment options,and thus improve depression.The pathophysiology of depression is characterized by the inhibition of neurological,functional and neurochemical abnormalities of aminobutyric acid（GABA）,which may lead to the degradation of signal integrity in the Nucleus accumens（NAc）brain region.The NAc region has a large number of GABA-capable neurons that can receive Hippocampus（HIP）excitatory neurons projections to form highly plastic and driving synapses.New studies show that abnormal neural activity through the HIP-NAc loop can predict the development of depression.The role of GABA,the major inhibitory neurotransmitter in the brain,in fear circuitry has been extensively studied,with GABA-ergic pathways playing a key role in fear acquisition,storage,and elimination.It plays a more lasting and slower role through the metabolite GABA_Breceptor（GABA_Breceptor,GABA_BR）.Methods:1.Depression model established and explored the expression of GABA_BR in HIP and NAc brain regions Chronic unforeseeable mild stress（CUMS）was successfully established to model depression.Time-dependent absenteeism,forced swimming,sugar water preference and body weight measurement,and cell component separation and protein immunoblotting were used to detect cell membrane GABA_BR expression changes in HIP and NAc brain regions.2.Clarify that the GABA_BR signaling pathway affects the occurrence and development of depression GABA_BR agonist Baclofen intervention,using the same experimental methods above for behavioral tests and cell membrane GABA_BR expression changes in HIP and NAc brain regions;3.Explore the cell membrane CaMKIIαexpression and its regulation of GABA_B1R phosphorylation level In the occurrence and development of depression and GABA_BR agonists intervention in depression,western blotting detected membrane GABA_B1R and CaMKIIαexpression in HIP and NAc brain regions,and co-immunoprecipitated CaMKIIαand GABA_B1R binding levels in HIP and NAc phosphate levels.Results:1.Chronic unpredictable mild stress（CUMS）was successfully established as a model of depression and rats showed time-dependent depression-like and anxiety-like behaviours 7d,14d and 21d after CUMS treatment.Further experiments confirmed that cell membrane GABA_BR expression was significantly decreased in HIP and NAc brain regions of CUMS depressed rats.2.GABA_BR agonists improved the appearance of depressive-like and anxiety-like behaviours in CUMS rats by increasing the level of GABA_BR expression in HIP and NAc cell membranes.3.Increased cell membrane CaMKIIαlevels in HIP brain regions during the development of depression decreased CaMKIIα-combined GABA_B1R levels and promoted GABA_B1R phosphorylation levels.In contrast,during GABA_BR intervention in the development of depression,HIP brain regions recovery cell membrane GABA_BR expression by promoting CaMKIIα-combined GABA_B1R to inhibit GABA_B1R phosphorylation.Conclusions:Decreased GABA_BR expression on cell membranes in HIP and NAc brain regions is closely associated with the development of chronic stress-induced depression;HIP brain regions reduce stable cell membrane GABA_BR expression through increased CaMKIIα-promoted GABA_B1R phosphorylation.