title: Acute and chronic stress differentially regulate cyclin-dependent kinase 5 in mouse brain: implications to glucocorticoid actions and major depression.
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.
authors.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.
authors.forename: A
authors.initials: A
authors.lastname: Papadopoulou
authors.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.
authors.forename: T
authors.identifier: 0000000177171869
authors.initials: T
authors.lastname: Siamatras
authors.affiliation: NeuroAdaptations Group, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: R
authors.identifier: 0000000285384087
authors.initials: R
authors.lastname: Delgado-Morales
authors.affiliation: Neuronal Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: N D
authors.initials: ND
authors.lastname: Amin
authors.affiliation: Neuronal Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: V
authors.initials: V
authors.lastname: Shukla
authors.affiliation: Neuronal Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Zheng
authors.affiliation: Neuronal Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: H C
authors.initials: HC
authors.lastname: Pant
authors.affiliation: NeuroAdaptations Group, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: O F X
authors.initials: OF
authors.lastname: Almeida
authors.affiliation: 1] Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA [2] Division of Experimental Biology, Department of Experimental Therapeutics, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: T
authors.initials: T
authors.lastname: Kino
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation; D010913:Pituitary-Adrenal System / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012149:Restraint, Physical; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse