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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

mRNA expression of glucocorticoid-responsive/stress-related genes in mice injected with corticosterone, or exposed to acute or chronic stress. (a and b) Corticosterone injection stimulates Avp and Id3 mRNA expression, respectively, in mouse PFC and HIPPO. Mice were injected intraperitoneally with corticosterone (CORT, 20 mg kg−1), and were killed at 0, 1, 3 and 24 h after the treatment. mRNA expression of indicated genes was measured with the SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of Avp and Id3 in PFC (a) and HIPPO (b) in the presence (closed bars) or absence (open bars) of CORT injection. *P<0.05, **P<0.01, compared with the conditions indicated. (c and d) Acute stress differentially regulates mRNA expression of stress-related genes in mouse PFC and HIPPO. Mice were immobilized in a 50 ml falcon tube for 1 h, and were killed at 0, 1, 3 and 24 h after the treatment. mRNA expression of indicated genes was measured in PFC (c) and HIPPO (d) with the SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes in PFC (c) and HIPPO (d). *P<0.05, **P<0.01, compared with the conditions indicated. (e and f) Chronic stress differentially regulates mRNA expression of glucocorticoid-responsive/stress-related genes in mouse PFC and HIPPO. Mice were treated with chronic unpredictable stress for 28 days, and were killed after the treatment. mRNA expression of indicated genes was measured in PFC (e) and HIPPO (f) with SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes of stressed mice to that of control unstressed mice in PFC (e) and HIPPO (f). *P<0.05, **P<0.01, compared with the condition without chronic stress. HIPPO, hippocampus; mRNA, messenger RNA; PFC, prefrontal cortex.
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fig4: mRNA expression of glucocorticoid-responsive/stress-related genes in mice injected with corticosterone, or exposed to acute or chronic stress. (a and b) Corticosterone injection stimulates Avp and Id3 mRNA expression, respectively, in mouse PFC and HIPPO. Mice were injected intraperitoneally with corticosterone (CORT, 20 mg kg−1), and were killed at 0, 1, 3 and 24 h after the treatment. mRNA expression of indicated genes was measured with the SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of Avp and Id3 in PFC (a) and HIPPO (b) in the presence (closed bars) or absence (open bars) of CORT injection. *P<0.05, **P<0.01, compared with the conditions indicated. (c and d) Acute stress differentially regulates mRNA expression of stress-related genes in mouse PFC and HIPPO. Mice were immobilized in a 50 ml falcon tube for 1 h, and were killed at 0, 1, 3 and 24 h after the treatment. mRNA expression of indicated genes was measured in PFC (c) and HIPPO (d) with the SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes in PFC (c) and HIPPO (d). *P<0.05, **P<0.01, compared with the conditions indicated. (e and f) Chronic stress differentially regulates mRNA expression of glucocorticoid-responsive/stress-related genes in mouse PFC and HIPPO. Mice were treated with chronic unpredictable stress for 28 days, and were killed after the treatment. mRNA expression of indicated genes was measured in PFC (e) and HIPPO (f) with SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes of stressed mice to that of control unstressed mice in PFC (e) and HIPPO (f). *P<0.05, **P<0.01, compared with the condition without chronic stress. HIPPO, hippocampus; mRNA, messenger RNA; PFC, prefrontal cortex.

Mentions: Among the glucocorticoid-responsive/stress-related genes that we used, CORT injection increased in PFC Id3 mRNA levels after 24 h and Avp mRNA levels after 3 and 24 h (Figure 4a), whereas it increased in HIPPO Id3 mRNA abundance after 3 and 24 h (Figure 4b). These results suggest that Id3, and possibly Avp in PFC, is the gene responsive to the elevation of circulating corticosterone in these brain areas, although several other genes, such as Bdnf, Crh and Sgk1, are reported to respond to glucocorticoids in vivo or in vitro.33, 34, 42, 46 We then examined mRNA expression of all these glucocorticoid-responsive/stress-related genes in PFC and HIPPO of the mice exposed to AS or CS. Results of the genes demonstrating statistically significant changes after exposure to AS are shown in Figures 4c and d. We also displayed results of the all-examined genes in Supplementary Figures 2a and b for convenience of comparison. AS markedly increased mRNA expression of Avp, Bdnf, FosB/ΔFosB, Nischarin and Rgd, and suppressed cFos and Ppp1r10 mRNA expression in PFC, whereas it increased Crh mRNA abundance and suppressed Avp, Id3, FosB/ΔFosB and Nischarin mRNA expression in HIPPO. These results suggest that the effect of AS on the mRNA expression of these genes is brain region-specific. Since the changes of mRNA expression profiles observed upon AS were completely different from those observed after CORT injection (particularly expression of Id3 and Avp), some regulatory mechanisms in addition to the elevation of circulating corticosterone are functional in the former case. In contrast to the effect of AS and CORT injection, CS stimulated mRNA expression of Htr1a and cFos in PFC and that of FosB/ΔFosB in HIPPO (Figures 4e and f), indicating that CS has quite different regulatory activity on the mRNA expression of glucocorticoid-responsive/stress-related genes compared with AS.


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)

mRNA expression of glucocorticoid-responsive/stress-related genes in mice injected with corticosterone, or exposed to acute or chronic stress. (a and b) Corticosterone injection stimulates Avp and Id3 mRNA expression, respectively, in mouse PFC and HIPPO. Mice were injected intraperitoneally with corticosterone (CORT, 20 mg kg−1), and were killed at 0, 1, 3 and 24 h after the treatment. mRNA expression of indicated genes was measured with the SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of Avp and Id3 in PFC (a) and HIPPO (b) in the presence (closed bars) or absence (open bars) of CORT injection. *P<0.05, **P<0.01, compared with the conditions indicated. (c and d) Acute stress differentially regulates mRNA expression of stress-related genes in mouse PFC and HIPPO. Mice were immobilized in a 50 ml falcon tube for 1 h, and were killed at 0, 1, 3 and 24 h after the treatment. mRNA expression of indicated genes was measured in PFC (c) and HIPPO (d) with the SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes in PFC (c) and HIPPO (d). *P<0.05, **P<0.01, compared with the conditions indicated. (e and f) Chronic stress differentially regulates mRNA expression of glucocorticoid-responsive/stress-related genes in mouse PFC and HIPPO. Mice were treated with chronic unpredictable stress for 28 days, and were killed after the treatment. mRNA expression of indicated genes was measured in PFC (e) and HIPPO (f) with SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes of stressed mice to that of control unstressed mice in PFC (e) and HIPPO (f). *P<0.05, **P<0.01, compared with the condition without chronic stress. HIPPO, hippocampus; mRNA, messenger RNA; PFC, prefrontal cortex.
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fig4: mRNA expression of glucocorticoid-responsive/stress-related genes in mice injected with corticosterone, or exposed to acute or chronic stress. (a and b) Corticosterone injection stimulates Avp and Id3 mRNA expression, respectively, in mouse PFC and HIPPO. Mice were injected intraperitoneally with corticosterone (CORT, 20 mg kg−1), and were killed at 0, 1, 3 and 24 h after the treatment. mRNA expression of indicated genes was measured with the SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of Avp and Id3 in PFC (a) and HIPPO (b) in the presence (closed bars) or absence (open bars) of CORT injection. *P<0.05, **P<0.01, compared with the conditions indicated. (c and d) Acute stress differentially regulates mRNA expression of stress-related genes in mouse PFC and HIPPO. Mice were immobilized in a 50 ml falcon tube for 1 h, and were killed at 0, 1, 3 and 24 h after the treatment. mRNA expression of indicated genes was measured in PFC (c) and HIPPO (d) with the SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes in PFC (c) and HIPPO (d). *P<0.05, **P<0.01, compared with the conditions indicated. (e and f) Chronic stress differentially regulates mRNA expression of glucocorticoid-responsive/stress-related genes in mouse PFC and HIPPO. Mice were treated with chronic unpredictable stress for 28 days, and were killed after the treatment. mRNA expression of indicated genes was measured in PFC (e) and HIPPO (f) with SYBR Green real-time PCR using their specific primers. Bars represent mean±s.e. values of fold mRNA expression of indicated genes of stressed mice to that of control unstressed mice in PFC (e) and HIPPO (f). *P<0.05, **P<0.01, compared with the condition without chronic stress. HIPPO, hippocampus; mRNA, messenger RNA; PFC, prefrontal cortex.
Mentions: Among the glucocorticoid-responsive/stress-related genes that we used, CORT injection increased in PFC Id3 mRNA levels after 24 h and Avp mRNA levels after 3 and 24 h (Figure 4a), whereas it increased in HIPPO Id3 mRNA abundance after 3 and 24 h (Figure 4b). These results suggest that Id3, and possibly Avp in PFC, is the gene responsive to the elevation of circulating corticosterone in these brain areas, although several other genes, such as Bdnf, Crh and Sgk1, are reported to respond to glucocorticoids in vivo or in vitro.33, 34, 42, 46 We then examined mRNA expression of all these glucocorticoid-responsive/stress-related genes in PFC and HIPPO of the mice exposed to AS or CS. Results of the genes demonstrating statistically significant changes after exposure to AS are shown in Figures 4c and d. We also displayed results of the all-examined genes in Supplementary Figures 2a and b for convenience of comparison. AS markedly increased mRNA expression of Avp, Bdnf, FosB/ΔFosB, Nischarin and Rgd, and suppressed cFos and Ppp1r10 mRNA expression in PFC, whereas it increased Crh mRNA abundance and suppressed Avp, Id3, FosB/ΔFosB and Nischarin mRNA expression in HIPPO. These results suggest that the effect of AS on the mRNA expression of these genes is brain region-specific. Since the changes of mRNA expression profiles observed upon AS were completely different from those observed after CORT injection (particularly expression of Id3 and Avp), some regulatory mechanisms in addition to the elevation of circulating corticosterone are functional in the former case. In contrast to the effect of AS and CORT injection, CS stimulated mRNA expression of Htr1a and cFos in PFC and that of FosB/ΔFosB in HIPPO (Figures 4e and f), indicating that CS has quite different regulatory activity on the mRNA expression of glucocorticoid-responsive/stress-related genes compared with AS.

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