title: The role of ventral striatal cAMP signaling in stress-induced behaviors.
abstract: The cAMP and cAMP-dependent protein kinase A (PKA) signaling cascade is a ubiquitous pathway acting downstream of multiple neuromodulators. We found that the phosphorylation of phosphodiesterase-4 (PDE4) by cyclin-dependent protein kinase 5 (Cdk5) facilitated cAMP degradation and homeostasis of cAMP/PKA signaling. In mice, loss of Cdk5 throughout the forebrain elevated cAMP levels and increased PKA activity in striatal neurons, and altered behavioral responses to acute or chronic stressors. Ventral striatum- or D1 dopamine receptor-specific conditional knockout of Cdk5, or ventral striatum infusion of a small interfering peptide that selectively targeted the regulation of PDE4 by Cdk5, produced analogous effects on stress-induced behavioral responses. Together, our results demonstrate that altering cAMP signaling in medium spiny neurons of the ventral striatum can effectively modulate stress-induced behavioral states. We propose that targeting the Cdk5 regulation of PDE4 could be a new therapeutic approach for clinical conditions associated with stress, such as depression.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Plattner
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Kanehiro
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Adan
authors.initials: A
authors.lastname: Hernández
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Benavides
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Tara C
authors.initials: TC
authors.lastname: Tassin
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Tan
authors.affiliation: Division of Neuroscience and Molecular Pharmacology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Day
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Maggy W
authors.initials: MW
authors.lastname: Fina
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York, USA.
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Yuen
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.affiliation: 1] Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Goldberg
authors.affiliation: 1] Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA. [2] Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Taussig
authors.affiliation: Department of Pharmacology, Kurume University School of Medicine, Fukuoka, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Nishi
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.affiliation: 1] Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA. [2] Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, Texas, USA. [3] Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism*; D066328:Ventral Striatum / Q000378:metabolism*
chemical_list: D000242:Cyclic AMP; D051360:Cyclin-Dependent Kinase 5; D017868:Cyclic AMP-Dependent Protein Kinases; C495906:Cdk5 protein, mouse; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4