Effects Of Chronic Mild Stress Induced Depression On Synaptic Plasticity In Mouse Hippocampus

Depression is a global mental disorder which endangers the physical and mental health of human beings.Global incidence is increasing year by year due to the rapid pace and pressure of social life.Typical symptoms of depression include depression,pessimism,self-sin and even suicide.The high recurrence,disability and fatality rate of depression make it the first major factor in the global burden of disease,putting tremendous pressure on families and society.However,anti-depressants commonly used in clinical practice often have slow onset,varied efficacy and low cure rate.A large number of patients even have refractory depression,and many side effects will lead to poor patient compliance and treatment interruption and recurrence.At present,there are many hypotheses about the pathogenesis of depression.Reduced hippocampal volume have found in suicide patients and animal experiments,dendritic atrophy,granule cell death,and also typical symptoms of depression including slow response and memory loss,all of which are related to synaptic plasticity,thus synaptic plasticity plays an important role in the pathogenesis of depression.However,most studies on synaptic plasticity focus on the prefrontal cortex and hippocampal pyramidal neurons,and studies on the dentate gyrus,especially the molecular layer,are rarely reported.Chronic mild stress(CMS)model is the most similar to the depression human suffered in daily life.This study intends to establish the CMS depression model,using the open field,elevated plus maze,tail suspension and forced swim tests to observe the anxiety and depression-like behavior in CMS mice;the levels of TH and TPH2 protein in cortex,hippocampus and midbrain were detected to observe the effects of depression on the release of neurotransmitters such as dopamine and serotonin.The changes of glial cells were detected by Western Blot and immunofluorescence in the expression of GFAP and Iba1 in hippocampus.The levels of synaptic plasticity-related proteins such as spinophilin,synaptophysin and synaptopodin were detected.Finally,Imaris reconstruction and transmission electron microscopy combined with Morris water maze were used to detect the changes of synapse and dendritic spines in the dentate gyrus as well as the ability of learning and memory to provide a theoretical basis for further elucidation of the changes in synaptic plasticity in the dentate gyrus of depression.The main results are as follows:1、CMS mice were dispirited and lost weight,the open field test and elevated plus maze showed that CMS impaired exploring ability and caused anxiety.Forced swim test and tail suspension test showed behavioral despair.Morris water maze showed that CMS impaired learning and memory.The expression of TH in cortex,hippocampus and midbrain of CMS mouse was decreased,the level of TPH2 was increased,indicating that CMS disturbed the release of neurotransmitters including 5-HT and DA.The protein expression and density of GFAP-positive cells in hippocampal DG and CA1 of CMS mice was decreased,the protein expression and density of Iba1-positive cells was increased,indicating a decreased density of hippocampal astrocytes and an increased density of microglia.2、Morris water maze showed that CMS impaired learning and memory.The level of synaptophysin and synaptopodin in the dentate gyrus of CMS mice showed no significant difference compared with control group.The level of spinophilin was significantly increased which indicated that CMS did not affect the number of synaptic vesicles and spine apparatus but increased the number of dendritic spines.Imaris three-dimensional reconstruction of immunofluorescence puncta and transmission electron microscopy showed that CMS increased the number of synapses and dendritic spines especially thin spines in the inner and outer molecular layers.In summary,this study explored the effects of depression on synaptic plasticity in the hippocampal dentate gyrus of mice by establishing a chronic unpredictable mild stress model.The results showed that the CMS model caused depression and anxiety in mice,disturbed the release of neurotransmitters including dopamine and serotonin,resulted in a decrease in the number of astrocytes and excessively activated microglia,meanwhile,CMS damaged the learning and memory ability of mice,increased the number of synapse and thin spines in the inner and outer molecular layers which may result from abnormal functional synaptic connections.