Journal
NATURE NEUROSCIENCE
Volume 18, Issue 8, Pages 1094-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.4066
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Funding
- UTSW Depression Center
- Brain and Behavior Research Foundation NARSAD Young Investigator Award
- pre-doctoral National Research Service Award from the National Institute on Drug Abuse
- Darrell K Royal Research Fund for Alzheimer's Research
- California Metabolic Research Foundation
- US National Institutes of Health grants [MH090963, DA10044, MH51399, GM084249, MH79710, MH083711, DA016672, DA018343, DA033485, NS073855]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM084249] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [P01MH040899, R01MH083711, P50MH090963, R01MH051399, R01MH108842, P50MH096890, R01MH079710] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [F32NS010161, R01NS073855] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA016672, P30DA018343, R01DA037618, P01DA010044, R01DA033485] Funding Source: NIH RePORTER
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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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