Increased Hippocampal Tau Phosphorylation And Axonal Mitochondrial Transport In A Mouse Model Of Chronic Stress

Corticotropin-releasing hormone (CRH) is considered as the driving force for hypothalamo-pituitary-adrenal (HPA) axis and play an important role in mood regulation. HPA axis is reported to be closely related to acute stress induced tau phosphorylation in rodent hippocampus. However, the relationship between the hyperactive HPA axis and tau phosphorylation in hippocampus and hence the functional implications in depression are not fully understood. In the present study, we aimed to examine the tau phosphorylation and the effect on axon transport of mitochondria in hippocampus of a depression model. A mice depression model was made by neonatal isolation before weaning, followed by chronic mild stress by social isolation after weaning. Behavior tests showed that the model had a typical depression-like behavior accompanied by increased plasma corticosterone level and hypothalamic CRH mRNA expression. The phosphorylated tau increased significantly, accompanied by increased synaptosome mitochondria level in hippocampus of the depression model. CRH receptor1 antagonist (CP154 526) treatment, not glucocorticoid receptor antagonist (RU486) treatment, decreased tau phosphorylation level, and restored synaptosome mitochondria level in model hippocampus. Moreover, when hyperphosphorylated tau was inhibited by lithium, the mitochondria transport monitored by live imaging was decreased in cultured primary hippocampus neuron. We showed here for the first time that the phosphorylated tau in model hippocampus, accompanied by increased mitochondria transport, was mediated by CRH receptor1, not by glucocorticoid receptor, which suggested that centrally derived CRH may be involved in the process of mitochondria axon transport and hence play an important role in the pathogenesis of depression.