Session: OR48-Novel Aspects of the HPA Axis: Bench to Smartphone
W470 (McCormick Place West Building)
Glucocorticoids have major actions in the brain, affecting cognition, mood, behavior and memory through the glucocorticoid receptor (GR), and play significant roles in pathophysiology of major depression. We previously reported that the neuronal cyclin-dependent kinase 5 (CDK5), essential for nervous system development, function, survival and pathogenesis of neurodegenerative disorders, modulates GR-induced transcriptional activity by phosphorylating multiple serine residues located in the N-terminal domain of this receptor (Kino T et al. Mol Endocrinol 21: 1552, 2007). To examine potential contribution of CDK5, GR and their interactions to stress response and pathophysiology of major depression, we measured enzymatic activity and protein expression of CDK5, phosphorylation of GR [at serine 211 (human) and 220 (mouse)] and mRNA expression of glucocorticoid-responsive and/or stress response-related genes in the prefrontal cortex (PFC) and hippocampus (Hippo) of female mice after intraperitoneal injection of corticosterone (20 mg/kg, n=3, at 1, 3 and 24 hours after injection), acute (restraint stress for 15 min, n=3, at 1, 3 and 24 hours after exposure) or chronic unpredictable (maternal separation for 30 days, n=3) stress, and those with veihcle injection or no stress exposure. We also measured these parameters in postmortem brain hippocampi from patients with major depression or control subjects (n=4, for each group). CDK5 activity and protein expression were reduced by 20% and 80% respectively, in PFC from 1hr-stressed mice, while they were upregulated by 30%, and 800% respectively, in Hippo of 3hr-stressed mice. Similar changes were observed in mice injected with corticosterone, suggesting that the activated glucocorticoid signaling system by acute stress is responsible for the observed changes in these CDK5 parameters. Levels of GR phosphorylation increased both in PFC (by 300%) and in Hippo (210%) after 1 hr-exposure of animals with acute stress or corticosterone injection, suggesting that other unknown kinase(s) distinct from CDK5 phosphorylated GR in response to these stimuli. Chronically stressed mice showed increaed CDK5 activity in PFC (by 80%) and Hippo (45%) and elevated protein levels in these brain regions (by 360% and 245%, respectively), indicating involvement of additional mechanism(s) compared to acute stress and corticosterone injection. These two CDK5 parameters were upregulated (by 16 and 1,050%, respectively) in Hippo of patients with major depression compared to control subjects, while levels of GR phosphorylation were similar in both groups. Taken together, these results suggest that acute and chronic stress differentially regulate the CDK5 activity/expression in a brain region-specific fashion, which may further contribute to pathophysiology of major depression.
Nothing to Disclose: AP, TS, RD, NDA, VS, HCP, OFXA, TK
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