The Role Of Leptin Receptor Tyrosine 985 Phosphorylation Site In The Regulation Of Emotional Behavior

Purposes:Depression has become the fourth human disease and it is expected to be the second disease following heart disease.In the study of depression,the monoamines hypothesis has made a significant contribution to research the progress of depression.The new approach to depression has been proposed according to this hypothesis.In addition,the receptor hypothesis suggests that the level of monoamine neurotransmitters is decrease which leads to the change of receptor function and number.The number of receptor will be up-regulated in some extent in the patient.Recently leptin and leptin receptor has become a hot focus in the study of depression,It is considered for leptin to be the main inhibitor of obesity,which is the product of ob gene expression.Leptin plays an important role in maintaining the normal structure and function of the hippocampus and the normal function of neurotransmitters.The leptin receptor function depends on the phosphorylation of tyrosine sites in the receptor structure,with the three most important sites being Tyr985,Tyr1077 and Tyr1138.The pathogenesis of depression may be associated with changes in signaling pathways that are regulated by these sites.If the JAK2/STAT3 signaling pathway is blocked by inhibitor,the depression of the mice is released.Studies have shown that Akt,GSK3β(glycogen synthase kinase),ERK1/2 signaling pathway play an important role in predicting the effect of antidepressant drugs.The aim of this study:(1)to investigate the changes of the signal transduction pathway(ERK,AKT,STAT3)in different brain regions after the mutation of Tyr985 site was confirmed;(2)to investigate the role of leptin receptor Tyr985 mutant mice(Y985F)in the pathogenesis of depression;(3)to investigate whether the depressive function of leptin and drugs(fluoxetine and Desipramine)was altered after the Tyr985 mutation.Methods:Male or female Y985F mice and control group wild mice to do the depression or anxiety test.Each mouse will be carried out genotype identification before the test.The changes of signal pathway molecules were observed by Western blot analysis after extraction of protein from hippocampus,prefrontal cortex(PFC)and hypothalamus.Behavioral experiment:1.basic depression or anxiety tests(sucrose/saccharin preference test,forced swimming test,tail suspension test,elevated plus-maze test,Light-dark test).2.depression or anxiety tests under stress conditions(learned helplessness,novelty-suppressed feeding test).3.depression test after abdominal cavity injection of antidepressant drugs.Results:Statistical analysis of protein content in different brain regions of Y985F mice and wild plants,there was no significant difference in P-ERT t308/T-AKT and P-AKT s473/T-AKT in hippocampus.It was significant difference in P-ERK/T-ERK between the two groups(P<0.05).The rate value of P-ERK/T-ERK,P-ERK2/T-ERK2 were significantly different in PFC brain region(P<0.05),but there was no significant difference in P-ERK1/T-ERK1,P-AKT/T-AKT level.In the hypothalamus,the level of P-ERK/T-ERK,P-AKT/T-AKT,P-STAT3/T-STAT3 show no significant difference.In the depression or anxiety test,the male and female mice group depression or anxiety behavior were no significant differences.In the depression test,there was no difference in Sucrose preference test、FST、TST in the male or female(P>0.05,WT group vs Y985F group).It was found that wild-type mice and Y985F mice still had similar depression under stress conditions in male or female(P>0.05).In the anxiety test,there was no difference in EPM and LD test in the male or female(P>0.05,WT group vs Y985F group).In the novelty-suppressed feeding test,the Y985F male and female mice also showed no significant anxiety.(P>(0.05 WT group vs Y985F group)In order to study the role of leptin and leptin receptor which is mutation at the 985 tyrosine site in the treatment of antidepressants,mice were conducted abdominal cavity injection of antidepressant drugs:leptin、fluoxetine and desipramine,compared with the injected saline group,both wild-type and Y985F mice had antidepressant effects after injection.Conclusions:(1)the phosphorylation level of ERK in the hippocampus and prefrontal cortex was decreased in the mouse hippocampus and prefrontal cortex after mutation of the Tyr985 site of the leptin receptor,which did not affect the phosphorylation level of ERK in the hypothalamus.(2)leptin receptor Tyr985 mutation did not affect basal and stress-induced depression and anxiety.(3)leptin receptor Tyr985 mutation does not affect leptin and antidepressant(fluoxetine and desipramine).