TSPO-mediated Fast-onset Antidepressant/anxiolytic-like And Cognitive-enhancing Effects And Its Mechanism Study

Objective Using gene knockout mice to explore the role TSPO plays in multiple psychiatric and cognitive disorders(depression,anxiety,post tramatic stress disorder(PTSD)or cognitive impairment)induced by chronic stress or central inflammation,and to exlplore the fast-onset antidepressant/anxiolytic and cognitive-enhancing effects of AC-5216,a well-accepted selective agonist of TSPO in chronically stressed mice.Methods(1)The PCR and Western Blot method were used to genotype TSPO(WT)mice and knock out(KO)mice and examine TSPO expression;(2)Chronical unpredicted stress or lipopolysaccharide-induced central inflammation were used to model depression/anxiety-like behaviors and cognitive impairment in mice;Foot shock was used to establish a mice model of PTSD,and freezing measurement was used to evaluate the PTSD-like fear behavior in mice.(3)The open field test(OFT)was used to evaluate locomotor activity;the OFT,elevated plus maze(EPM)and novelty-suppressed feeding(NSF)were used to evaluated anxiety-like behaviors;the tail suspension test(TST),forced swim test(FST),NSF and sucrose preference test(SPT)were used to evaluate depression-like behaviors;novel object recognition(NOR)and step down latency test(SD)were used to evaluate cognitive function;(4)ELISA was used to examine the corticosterone level in serum,allopregnanolone level in prefrontal cortex(PFC)and hippocampus,and TNF-? and IL-1? levels in PFC;(5)Western Blot was used to examine the m BDNF,m TOR,p-m TOR,PSD-95,synapsin-1 and Glu R-1 levels in PFC to evaluate the activation of BDNF-m TOR signaling pathway;(6)Golgi' staining was used to examine total dendritic length and the number of dendritic branching points of PFC pyramidal neurons to evaluate dendritic complexity.Results(1)Compared with TSPO WT mice,KO mice had no expressible TSPO gene and no TSPO expression was found in various organs of multiple systems.(2)In physiological consitions,TSPO WT and KO mice showed similar depression/anxiety-like behaviors and cognitive function;(3)TSPO WT and KO mice showed similar depression/anxiety-like behaviors and cognitive impairment under chronial unpredeicted stress(CUS),and similar enhancement of PTSD-like freezing behaviors in foot-shock-induced PTSD model.(4)In TSPO WT not KO mice,LPS induced depression/anxiety-like behaviors and cognitive impairment,and increased the levels of TSPO,allopregnanolone,TNF-? and IL-1? in hippocampus.(5)In TSPO WT not KO mice,a single dose of AC-5216(0.3mg/kg)exerted significant antidepressantand anxiolytic-like effects.(6)In chronically stressed TSPO WT not KO mice,2-4 days treatment of AC-5216(0.3mg/kg)exerted fast-onset antidepressant/anxiolytic-like and cognitive-enhancing effects.(7)In chronically stressed TSPO WT not KO mice,5 days treatment of AC-5216(0.3mg/kg)significantly decreased corticosterum levels in serum,and increased allopregnanolone,BDNF-m TOR signaling pathway related proteins(BDNF,p-m TOR,PSD-95,synapsin-1,Glu R1),the total dendritic length and the number of dendritic branching points of pyramidal neurons in PFC.Conclusions The present study firstly showed that TSPO WT and KO mice had similar sensitivity to CUS-induced psychiatric disorders and electiric-induced PTSD-like behaviors while TSPO mediated LPS-induced central inflammation and psychiatric disorders,suggesting distinct roles TSPO plays in various psychiatric disorders caused by different incentives.In addition,we found for the first time that TSPO mediated AC-5216(0.3mg/kg)-induced fast-onset(2-4d)antidepressant/anxiolytc-like and cognitive-enhancing effects in chronically stressed mice,the mechenisms of which lied probably in the fast activation of BDNF-m TOR signaling pathway and increasement of synaptic formation and dendritic complexity of pyramidal neurons in PFC,demonstrating the pharmacological target value and charateristics of TSPO.