Chronic Non-predictable Stress, Nmda Receptor Kalirin And Nos Expression

Depression is associated with significant morbidity and functional disability, and it is thus important to reveal the mechanism of depression. The hippocampus has recently attracted tremendous attention for the study of depression. A variety of studies suggest an involvement of glutamic acid (Glu)and N-methyl-D-aspartic acid (NMDA) receptor in the pathophysiological mechanism of depression development. Since accumulated evidence indicates a role of nitric oxide (NO) in brain impairment produced by chronic stress. Chronic stress can increase expression of nitric oxide synthase (NOS) in hippocampus, and stimulate NO release may be involved in development of depression. It is unknown, however, whether the relationship of NMDA receptor and NOS also makes contributions to the mechanism of Chronic Stress-induced depression, and the behavioural ability of the rodents. Kalirin is necessary for maintenance of dendritic spines and dendritic branches. Previous research revealed that the atrophy of dendrities could be induced by chronic stress or ovariectomy, but that whether Kalirin is involved in the pathology of chronic stress-induced depression through influencing the changes of dendrities, and the relationship between NMDAR and kalirin is not known until recently.This study show that intra-hippocampal injections of the NMDA receptor agonist (N-methyl-D-aspartic acid), and antagonist MK-801 during chronic unexpected mild stress (CUMS) affect behavioral changes including body weight, sucrose preference, locomotor activity, rearing and grooming in open field test, and duration of immobility in forced swimming test. The expression of neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) and kalirin in rat hippocampus also were observed by immunohistochemistry.Rats receiving CUMS for 21 days display a variety of behavioral measures of depression, including a significant reduction in body weight, sucrose preference, and locomotion, rearing and grooming in open field test, and a significant increase in immobility time in forced swimming test, and the expression of nNOS and iNOS increased and expression of kalirin decreased in hippocampus. The behavioral ability of the intra-hippocampal injections of NMDA receptor agonist rats dramatically depressed and the expression of nNOS in dental gyrus (DG) increased, the expression of iNOS increased in both DG and CA3 area of hippocampus, the expression of kalirin significantly reduction. Intra-hippocampal injection of noncompetitive NMDA antagonist MK-801 significantly prevent CUMS-induced depression-like behavioral changes, decreased the expression of nNOS in both DG and CA3 area and the expression of iNOS in CA3 area, and significant increase in that of kalirin-IR cells in hippocampus.Both CUMS and intra-hippocampal injections of NMDA receptor agonist can induce depression-like behavioral changes, increased the expression of NOS and reduction in the expression of kalirin in hippocampus. NMDA receptor antagonist decreased the expression of NOS, suppressed CUMS-induced depression-like behavioral changes. This study provide the evidence suggesting that CUMS which results in development of depression may induce neurotoxicity in hippocampal neurons by stimulating Glu release, inducing excessively activation of NMDA receptor, reducing expression of kalirin, increasing expression of NOS, and influence the neural plasticity in CNS.