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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

Depressive patients show variable CDK5 activity, its protein expression, GR phosphorylation and mRNA expression of glucocorticoid-responsive/stress-related genes in some brain areas. (a) Depressive patients demonstrate altered CDK5 acitivity in BA25, but not in PFC, HIPPO and IFG. The CDK5 acitivity was evaluated in HIPPO, PFC, BA25 and IFG of deceased patients with major depression or deceased control subjects. Bars represent mean±s.e. values of fold kinase activity in depressive patients (closed bars) or in control subjects (open bars; mean values of control subjects as ‘1'). **P<0.01, n.s., not significant, compared with the conditions indicated. (b and c) Depressive patients have unaltered CDK5 protein levels but reduced GR phosphorylation in HIPPO. Levels of the CDK5 protein (b) and the GR phosphorylated at serine 211 (P-GR) (c) were evaluated in HIPPO of deceased patients with major depression or deceased control subjects. Bars represent mean±s.e. values of relative CDK5 protein and P-GR levels in depressive patients (closed bars) or in control subjects (open bars). **P<0.01; n.s., not significant, compared with the conditions indicated. (d and e) Depressive patients demonstrate altered mRNA expression of glucocorticoid-responsive/stress-related genes in HIPPO and BA25. mRNA expression of the indicated genes was measured in HIPPO (d) and BA25 (e) of deceased patients with major depression and deceased control subjects with SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes of depressive patients to those of control subjects. *P<0.05, **P<0.01; n.s., not significant, compared with control subjects. GR, glucocorticoid receptor; HIPPO, hippocampus; IFG, inferior frontal gyrus; mRNA, messenger RNA; PFC, prefrontal cortex.
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fig5: Depressive patients show variable CDK5 activity, its protein expression, GR phosphorylation and mRNA expression of glucocorticoid-responsive/stress-related genes in some brain areas. (a) Depressive patients demonstrate altered CDK5 acitivity in BA25, but not in PFC, HIPPO and IFG. The CDK5 acitivity was evaluated in HIPPO, PFC, BA25 and IFG of deceased patients with major depression or deceased control subjects. Bars represent mean±s.e. values of fold kinase activity in depressive patients (closed bars) or in control subjects (open bars; mean values of control subjects as ‘1'). **P<0.01, n.s., not significant, compared with the conditions indicated. (b and c) Depressive patients have unaltered CDK5 protein levels but reduced GR phosphorylation in HIPPO. Levels of the CDK5 protein (b) and the GR phosphorylated at serine 211 (P-GR) (c) were evaluated in HIPPO of deceased patients with major depression or deceased control subjects. Bars represent mean±s.e. values of relative CDK5 protein and P-GR levels in depressive patients (closed bars) or in control subjects (open bars). **P<0.01; n.s., not significant, compared with the conditions indicated. (d and e) Depressive patients demonstrate altered mRNA expression of glucocorticoid-responsive/stress-related genes in HIPPO and BA25. mRNA expression of the indicated genes was measured in HIPPO (d) and BA25 (e) of deceased patients with major depression and deceased control subjects with SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes of depressive patients to those of control subjects. *P<0.05, **P<0.01; n.s., not significant, compared with control subjects. GR, glucocorticoid receptor; HIPPO, hippocampus; IFG, inferior frontal gyrus; mRNA, messenger RNA; PFC, prefrontal cortex.

Mentions: Since chronic stress is associated with pathophysiology of major depression and GR is a potential target of anti-depressant drugs,22, 47, 48 we measured CDK5 activity in PFC and HIPPO of postmortem brains of subjects with major depression (Figure 5a). In addition, we measured CDK5 activity in two specific subregions of the PFC implicated in mood and symptoms related to mood disorders, namely the subgenual anterior cingulate cortex (BA25) and the inferior frontal gyrus (corresponding to BA44, 45 and 47) to avoid a possibility of overlooking the phenomena specific to these brain areas.49, 50, 51, 52 We found that the CDK5 activity was elevated in BA25 of these depressive subjects, while the activity in their PFC, HIPPO and inferior frontal gyrus was similar to that of control subjects. Our ability to detect the change in BA25 most likely reflects its ‘small size' and ‘dilution effects' when whole PFC was analyzed.


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)

Depressive patients show variable CDK5 activity, its protein expression, GR phosphorylation and mRNA expression of glucocorticoid-responsive/stress-related genes in some brain areas. (a) Depressive patients demonstrate altered CDK5 acitivity in BA25, but not in PFC, HIPPO and IFG. The CDK5 acitivity was evaluated in HIPPO, PFC, BA25 and IFG of deceased patients with major depression or deceased control subjects. Bars represent mean±s.e. values of fold kinase activity in depressive patients (closed bars) or in control subjects (open bars; mean values of control subjects as ‘1'). **P<0.01, n.s., not significant, compared with the conditions indicated. (b and c) Depressive patients have unaltered CDK5 protein levels but reduced GR phosphorylation in HIPPO. Levels of the CDK5 protein (b) and the GR phosphorylated at serine 211 (P-GR) (c) were evaluated in HIPPO of deceased patients with major depression or deceased control subjects. Bars represent mean±s.e. values of relative CDK5 protein and P-GR levels in depressive patients (closed bars) or in control subjects (open bars). **P<0.01; n.s., not significant, compared with the conditions indicated. (d and e) Depressive patients demonstrate altered mRNA expression of glucocorticoid-responsive/stress-related genes in HIPPO and BA25. mRNA expression of the indicated genes was measured in HIPPO (d) and BA25 (e) of deceased patients with major depression and deceased control subjects with SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes of depressive patients to those of control subjects. *P<0.05, **P<0.01; n.s., not significant, compared with control subjects. GR, glucocorticoid receptor; HIPPO, hippocampus; IFG, inferior frontal gyrus; mRNA, messenger RNA; PFC, prefrontal cortex.
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Related In: Results  -  Collection

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fig5: Depressive patients show variable CDK5 activity, its protein expression, GR phosphorylation and mRNA expression of glucocorticoid-responsive/stress-related genes in some brain areas. (a) Depressive patients demonstrate altered CDK5 acitivity in BA25, but not in PFC, HIPPO and IFG. The CDK5 acitivity was evaluated in HIPPO, PFC, BA25 and IFG of deceased patients with major depression or deceased control subjects. Bars represent mean±s.e. values of fold kinase activity in depressive patients (closed bars) or in control subjects (open bars; mean values of control subjects as ‘1'). **P<0.01, n.s., not significant, compared with the conditions indicated. (b and c) Depressive patients have unaltered CDK5 protein levels but reduced GR phosphorylation in HIPPO. Levels of the CDK5 protein (b) and the GR phosphorylated at serine 211 (P-GR) (c) were evaluated in HIPPO of deceased patients with major depression or deceased control subjects. Bars represent mean±s.e. values of relative CDK5 protein and P-GR levels in depressive patients (closed bars) or in control subjects (open bars). **P<0.01; n.s., not significant, compared with the conditions indicated. (d and e) Depressive patients demonstrate altered mRNA expression of glucocorticoid-responsive/stress-related genes in HIPPO and BA25. mRNA expression of the indicated genes was measured in HIPPO (d) and BA25 (e) of deceased patients with major depression and deceased control subjects with SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes of depressive patients to those of control subjects. *P<0.05, **P<0.01; n.s., not significant, compared with control subjects. GR, glucocorticoid receptor; HIPPO, hippocampus; IFG, inferior frontal gyrus; mRNA, messenger RNA; PFC, prefrontal cortex.
Mentions: Since chronic stress is associated with pathophysiology of major depression and GR is a potential target of anti-depressant drugs,22, 47, 48 we measured CDK5 activity in PFC and HIPPO of postmortem brains of subjects with major depression (Figure 5a). In addition, we measured CDK5 activity in two specific subregions of the PFC implicated in mood and symptoms related to mood disorders, namely the subgenual anterior cingulate cortex (BA25) and the inferior frontal gyrus (corresponding to BA44, 45 and 47) to avoid a possibility of overlooking the phenomena specific to these brain areas.49, 50, 51, 52 We found that the CDK5 activity was elevated in BA25 of these depressive subjects, while the activity in their PFC, HIPPO and inferior frontal gyrus was similar to that of control subjects. Our ability to detect the change in BA25 most likely reflects its ‘small size' and ‘dilution effects' when whole PFC was analyzed.

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