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Acute and chronic stress differentially regulate cyclin-dependent kinase 5 in mouse brain: implications to glucocorticoid actions and major depression.

Papadopoulou A, Siamatras T, Delgado-Morales R, Amin ND, Shukla V, Zheng YL, Pant HC, Almeida OF, Kino T - Transl Psychiatry (2015)

Bottom Line: Cyclin-dependent kinase 5 (CDK5), a molecule essential for nervous system development, function and pathogenesis of neurodegenerative disorders, can modulate GR activity through phosphorylation.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.

View Article: PubMed Central - PubMed

Affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Chronic stress differentially regulates CDK5 activity and protein expression in mouse PFC and HIPPO. Mice were treated with chronic unpredictable stress for 28 days. CDK5 activity (a) and protein expression (b) were examined, respectively, with the CDK5 kinase assay and with the western blot using anti-CDK5 antibody. Bars represent mean±s.e. values of fold kinase activity against baseline (the condition in the absence of chronic stress) and the protein levels of CDK5 in the presence (closed bars) or absence (open bars) of chronic stress. *P<0.05, **P<0.01, compared with the conditions indicated. HIPPO, hippocampus; PFC, prefrontal cortex.
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fig2: Chronic stress differentially regulates CDK5 activity and protein expression in mouse PFC and HIPPO. Mice were treated with chronic unpredictable stress for 28 days. CDK5 activity (a) and protein expression (b) were examined, respectively, with the CDK5 kinase assay and with the western blot using anti-CDK5 antibody. Bars represent mean±s.e. values of fold kinase activity against baseline (the condition in the absence of chronic stress) and the protein levels of CDK5 in the presence (closed bars) or absence (open bars) of chronic stress. *P<0.05, **P<0.01, compared with the conditions indicated. HIPPO, hippocampus; PFC, prefrontal cortex.

Mentions: We next examined impact of CS to the CDK5 activity in mouse PFC and HIPPO. CS markedly increased the CDK5 activity both in these brain regions (Figure 2a), indicating that chronic exposure to stress is a strong stimulator of this kinase activity. CS also increased CDK5 protein levels both in PFC and HIPPO (Figure 2b).


Acute and chronic stress differentially regulate cyclin-dependent kinase 5 in mouse brain: implications to glucocorticoid actions and major depression.

Papadopoulou A, Siamatras T, Delgado-Morales R, Amin ND, Shukla V, Zheng YL, Pant HC, Almeida OF, Kino T - Transl Psychiatry (2015)

Chronic stress differentially regulates CDK5 activity and protein expression in mouse PFC and HIPPO. Mice were treated with chronic unpredictable stress for 28 days. CDK5 activity (a) and protein expression (b) were examined, respectively, with the CDK5 kinase assay and with the western blot using anti-CDK5 antibody. Bars represent mean±s.e. values of fold kinase activity against baseline (the condition in the absence of chronic stress) and the protein levels of CDK5 in the presence (closed bars) or absence (open bars) of chronic stress. *P<0.05, **P<0.01, compared with the conditions indicated. HIPPO, hippocampus; PFC, prefrontal cortex.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490283&req=5

fig2: Chronic stress differentially regulates CDK5 activity and protein expression in mouse PFC and HIPPO. Mice were treated with chronic unpredictable stress for 28 days. CDK5 activity (a) and protein expression (b) were examined, respectively, with the CDK5 kinase assay and with the western blot using anti-CDK5 antibody. Bars represent mean±s.e. values of fold kinase activity against baseline (the condition in the absence of chronic stress) and the protein levels of CDK5 in the presence (closed bars) or absence (open bars) of chronic stress. *P<0.05, **P<0.01, compared with the conditions indicated. HIPPO, hippocampus; PFC, prefrontal cortex.
Mentions: We next examined impact of CS to the CDK5 activity in mouse PFC and HIPPO. CS markedly increased the CDK5 activity both in these brain regions (Figure 2a), indicating that chronic exposure to stress is a strong stimulator of this kinase activity. CS also increased CDK5 protein levels both in PFC and HIPPO (Figure 2b).

Bottom Line: Cyclin-dependent kinase 5 (CDK5), a molecule essential for nervous system development, function and pathogenesis of neurodegenerative disorders, can modulate GR activity through phosphorylation.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.

View Article: PubMed Central - PubMed

Affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

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.

No MeSH data available.


Related in: MedlinePlus