Postsynaptic Density-93 In Paraventricular Nucleus Of Hypothalamus Involved In The Pathogenesis Of Depression

Globally approximately 20%of the population are threaten by depression,which is a typical chronic and recurrent neuropsychiatric disease.In the stress hypothesis of depression,the hyperactivity of corticotropin-releasing hormone(CRH)neuron in paraventricular nucleus of hypothalamus(PVN)has been considered as a primary cause of disturbed hypothalamic-pituitary-adrenal(HPA)axis.However,it remains unclear about the molecular regulation mechanism of CRH neuron in depression.Abnormal structure and function of excitatory synapse in different brain areas have been reported in animal depression model.As a member of postsynaptic density protein family,postsynaptic density-93(PSD-93)has been found with an abnormal expression in the brain of major depression patient.But the relationship between hypothalamic PSD93 expression and depression-like behavior need to be further elucidated.In the present study,we performed immunostaining assay,animal behavior test,molecular assays and whole-cell-patch-clamp recording to explore the role of PSD-93 in PVN CRH neurons in the pathogenesis of depression.We firstly observed abundant PSD-93-immunoreactive neurons and PSD-93/CRH double positive neurons in the PVN of mice and human brain by immunostaining and an increased number of PSD-93/CRH double positive neurons was found in major depression patients,which suggested the involvement of PSD-93 in the pathogenesis of depression.In order to explore the causality of co-localization and pathogenesis of depression,we conducted the PSD-93 overexpression and knockdown by AAV virus injection in the PVN.It was found that PSD-93 overexpression in PVN CRH neurons induced depression-like behaviors,accompanied with the increased serum corticosterone level.Inversely,knockdown of PSD-93 expression in PVN lead to the anti-depression behavior and the decreased serum corticosterone level.These results indicated that PSD-93 could regulate the depression-like behavior in mice.In order to explore physiological mechanism of CRH neuron regulated by PSD-93,based on whole-cell-patch-clamp recording,overexpression of PSD-93 in PVN increased synaptic activity in CRH neurons,as showed that cumulative distribution of mEPSC interevents interval and average frequency of CRH neuron increased.Knocking-down of PSD-93 in PVN reduced synaptic activity of CRH neurons,as showed that cumulative distribution of mEPSC interevents interval and average frequency of CRH neurons decreased.We also observed that the glutamate receptor(GluRl and NR2A)protein in hypothalamus were significantly increased in PSD-93-ovexpression group and decreased in PSD-93-knockdown group.These results indicated that PSD-93 regulated CRH synaptic activity by glutamate receptor in pathogenesis of depression.In order to verify the effect of PSD-93-knockdown in depression model,we tested the effect in the LPS and social defeat stress induced depression model.The result showed that PSD-93-knockdown in PVN rescued the depression-like behavior.The immobility time in forced swimming test and tail suspension test was decreased in PSD-93-knockdown group.Furthermore,in order to explore the type of glutamate receptor involved in the pathogenesis of depression,we inhibited the function of NMDAR by local infusion of ketamine,antagonist of NMDAR,into PVN.The result showed that the depression-like behavior was rescued.These results indicated that knockdown of PSD-93 decreased CRH synaptic activity by NR2A and then induced the anti-depression effect.These results indicated that overexpression of PSD-93 in PVN might increase the synaptic activity of CRH neuron by the glutamate receptor NR2A and then intensify the depression-like behavior by increasing the activity of HPA axis.On the contrary,knockdown of PSD-93 in PVN might decrease synaptic activity of CRH neuron by glutamate receptor NR2A and then induce the anti-depression behavior by suppression of activity of HPA axis.The present study reveals a new idea in the pathogenesis of depression and may provide a potential target for the anti-depression therapy.