The role of ventral striatal cAMP signaling in stress-induced behaviors

Florian Plattner, Kanehiro Hayashi, Adan Hernández, David R Benavides, Tara C Tassin, Chunfeng Tan, Jonathan Day, Maggy W Fina, Eunice Y Yuen, Zhen Yan, Matthew S Goldberg, Angus C Nairn, Paul Greengard, Eric J Nestler, Ronald Taussig, Akinori Nishi, Miles D Houslay, James A Bibb

Research output: Contribution to journalArticlepeer-review

62 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1094-11100
Number of pages7
JournalNature Neuroscience
Issue number8
Early online date20 Jul 2015
Publication statusPublished - 1 Aug 2015


  • cAMP
  • protein kinase A
  • cAMP/PKA signaling


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