The role of ventral striatal cAMP signaling in stress-induced behaviors
Open accessAbstract
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.
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Nucleus accumbens D1 medium spiny neuron-specific knockout of Cdk5 reduces cAMP levels, increases PKA activity, and promotes antidepressant outcomes.
“NAc D1-MSN specific knockout of Cdk5 reduces cAMP levels, increases PKA activity, and promotes antidepressant outcomes (63).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [63]
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Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression
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- Authors
- Plattner, F., Hayashi, K., Hernández, A., Benavides, D. R., Tassin, T. C., Tan, C., Day, J., Fina, M. W., Yuen, E. Y., Yan, Z., Goldberg, M. S., Nairn, A. C., Greengard, P., Nestler, E. J., Taussig, R., Nishi, A., Houslay, M. D., & Bibb, J. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Keio University (JP)
- University of Glasgow (GB)
- University at Buffalo, State University of New York (US)
- Yale University (US)
- Rockefeller University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Kurume University (JP)
- King's College London (GB)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Corresponding author
- Bibb, James A
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2015-07-20
- Volume
- 18
- Issue
- 8
- Pages
- 1094-1100
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4519694
- OpenAlex
- W1913344680
- Cited by
- 94
- References
- 65
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 7 · 2023: 10 · 2022: 9 · 2021: 10 · 2020: 2 · 2019: 10 · 2018: 6 · 2017: 11 · 2016: 11 · 2015: 3
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Institute of Mental Health (MH79710, P50MH090963, P50MH096890, MH51399, MH090963, R01MH083711, R01MH051399, MH083711, R01MH108842, P01MH040899, R01MH079710)
- National Institute on Drug Abuse (R01DA037618, R01DA033485, DA10044, DA016672, P01DA010044, DA033485, DA 018343, R01DA016672, P30DA018343)
- National Institute of General Medical Sciences (GM084249, R01GM084249)
- National Institute of Neurological Disorders and Stroke (R01NS073855, NS073855, F32NS010161)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- cAMP signaling, ventral striatum, cyclin-dependent kinase 5, phosphodiesterase 4, cAMP degradation, protein kinase A, dopamine D1 receptor, stress response, chronic stress, acute stress, depression, medium spiny neurons, conditional knockout, neuromodulation
- MeSH terms
- Cyclic AMP, Animals, Behavior, Animal, Male, Mice, Inbred C57BL, Stress, Psychological, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Mice, Knockout, Cyclin-Dependent Kinase 5, Mice, Cyclic Nucleotide Phosphodiesterases, Type 4, Ventral Striatum
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