The Role And Mechanism Of Kalirin-7 In Ketamine's Anti-stress Depression

Depression is a common and serious mental illness characterized by persistent depression and cognitive impairment.The study found that the occurrence of depression is related to the brain area of the emotional neural circuit,including the prefrontal cortex,hippocampus,nucleus accumbens and amygdala.In recent years,the incidence of depression shows an upward trend,but the pathogenesis of depression has not been fully elucidated.Ketamine,a noncompetitive NMDA receptor antagonist,has a rapid and effective antidepressant effect that reverses CUMS-induced changes in dendrity and dendritic spine,whereas Kalirin-7 is the key factors to regulate dendritic spines and synaptic structures.However,whether or not Kalirin-7 changes in the related brain regions such as the medial prefrontal cortex,hippocampus,nucleus accumbens and amygdala in the antidepressant effect of ketamine is not clearly related to the plasticity of neuronal dendritic spines.To investigate whether ketamine reverses the changes in dendritic plasticity induced by CUMS through the Kalirin-7 signaling pathway,and the relationship between Kalirin-7 and the changes of the neuronal dendritic spine plasticity in the four major brain regions namely,the medial prefrontal cortex,hippocampus,nucleus accumbens and amygdala,associate with depression of neural circuit in depression induced by stress.We established the model of chronic unpredictable mild stress(CUMS)depression,and some rats got a single intraperitoneal injection of ketamine.Sucrose preference test,body weight measurement and tail-suspension test were used to examine the behavioral changes of the animals.Golgi staining was used to detect the density of dendritic spines of neurons in hippocampal CA3 area,medial prefrontal cortex PL area,nucleus accumbens core area and amygdala BLA area.Western blot was used to detect the levels of Kalirin-7 and glutamate receptor NR1 in the relevant brain regions.The results show:1.CUMS could cause depression-like behaviors in rats,compared with the control group,the sucrose preference rate decreased significantly,while the immobility time in the tail suspension test increased significantly.The contents of Kalirin-7,NR1 and the dendritic spines density were decreased in the medial prefrontal cortex and hippocampus.In nucleus accumbens and amygdala,the contents of Kalirin-7 and NR1 and the dendritic spine density were increased.2.A single low-dose(10mg/kg)intraperitoneal injection of ketamine could significantly relieve CUMS-induced depression-like symptoms,and significantly increased the expression of Kalirin-7,NR1 and the dendritic spines density in pyramidal neurons in the hippocampus and medial prefrontal cortex of CUMS rats;in nucleus accumbens and amygdala the contents of Kalirin-7,NR1 and the dendritic spine density decreased significantly.The above results show that the depression-like behavior induced by CUMS is associated with plasticity changes of neuron dendritic spines in multiple brain regions of the neural circuit,and the changes in different regions are different.The occurrence of stress depression was associated with decreased expression of Kalirin-7 and dendritic spine densities of neurons in the hippocampus and medial prefrontal cortex,increased expression of Kalirin-7 and dendritic spine density of neurons in the nucleus accumbens,amygdala.Kalirin-7 plays an important role in the changes of neuron dendritic spines in the corresponding brain regions of the neural circuits induced by ketamine reversal of CUMS,and is involved in the reconstruction of glutamatergic synapses.The antidepressant effect of ketamine may be achieved by altering the expression of Kalirin-7 in the relevant brain regions and promoting the formation of dendritic spines and glutamate receptors.