Abstract
Stress activates the hypothalamic–pituitary–adrenal axis, which in turn increases circulating glucocorticoid concentrations and stimulates the glucocorticoid receptor (GR). Chronically elevated glucocorticoids by repetitive exposure to stress are implicated in major depression and anxiety disorders. Cyclin-dependent kinase 5 (CDK5), a molecule essential for nervous system development, function and pathogenesis of neurodegenerative disorders, can modulate GR activity through phosphorylation. We examined potential contribution of CDK5 to stress response and pathophysiology of major depression. In mice, acute immobilized stress (AS) caused a biphasic effect on CDK5 activity, initially reducing but increasing afterwards in prefrontal cortex (PFC) and hippocampus (HIPPO), whereas chronic unpredictable stress (CS) strongly increased it in these brain areas, indicating that AS and CS differentially regulate this kinase activity in a brain region-specific fashion. GR phosphorylation contemporaneously followed the observed changes of CDK5 activity after AS, thus CDK5 may in part alter GR phosphorylation upon this stress. In the postmortem brains of subjects with major depression, CDK5 activity was elevated in Brodmann's area 25, but not in entire PFC and HIPPO. Messenger RNA expression of glucocorticoid-regulated/stress-related genes showed distinct expression profiles in several brain areas of these stressed mice or depressive subjects in which CDK5-mediated changes in GR phosphorylation may have some regulatory roles. Taken together, these results indicate that CDK5 is an integral component of stress response and major depression with regulatory means specific to different stressors, brain areas and diseases in part through changing phosphorylation of GR.
Highlights
Unpredicted short- and long-term stressful events have a significant influence over our daily activities.[1,2,3] The physiological response to stress includes integration of neural and humoral information at multiple levels in the brain and periphery, with the hypothalamic–pituitary–adrenal (HPA) axis playing a major role in coordination of central and peripheral components.[4]
To evaluate impact of acute and chronic stress on Cyclin-dependent kinase 5 (CDK5) kinase activity, we focused on two brain areas, the prefrontal cortex (PFC) and the HIPPO, because they are both major targets of stress,[1] and are implicated in mood, emotion and cognitive functions.[43,44]
CORT injection increased glucocorticoid receptor (GR) phosphorylation after 1 h in PFC, while the injection increased it after 1 h and 3 h in HIPPO (Figures 3a and b), consistent with a well-known fact that GR is phosphorylated just after binding to ligand.[45]. These results indicate that the elevation of CDK5 activity by acute immobilized stress (AS), respectively, observed after 24 h and 3 h in PFC and HIPPO may account for the Distinct messenger RNA (mRNA) expression profiles of the glucocorticoidresponsive/stress-related genes in acute and chronic stress
Summary
Unpredicted short- and long-term stressful events have a significant influence over our daily activities.[1,2,3] The physiological response to stress includes integration of neural and humoral information at multiple levels in the brain and periphery, with the hypothalamic–pituitary–adrenal (HPA) axis playing a major role in coordination of central and peripheral components.[4]. Glucocorticoid secretion is sometimes unrestrained and maladaptive if the stress stimulus exceeds threshold of individual quality, intensity and/or chronicity, leading to development of an array of adverse effects, such as mood alteration, induction of anxiety and cognitive dysfunction, as well as immune suppression, osteoporosis and central obesity-associated insulin resistance and hyperlipidemia.[2,5,6]
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