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

doi:10.1038/nn.4066

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

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

71 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1094-11100
Number of pages	7
Journal	Nature Neuroscience
Volume	18
Issue number	8
Early online date	20 Jul 2015
DOIs	https://doi.org/10.1038/nn.4066
Publication status	Published - 1 Aug 2015

Keywords

cAMP
protein kinase A
cAMP/PKA signaling

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10.1038/nn.4066

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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. (2015). The role of ventral striatal cAMP signaling in stress-induced behaviors. Nature Neuroscience, 18(8), 1094-11100. https://doi.org/10.1038/nn.4066

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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.",

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author = "Florian Plattner and Kanehiro Hayashi and Adan Hern{\'a}ndez and Benavides, {David R} and Tassin, {Tara C} and Chunfeng Tan and Jonathan Day and Fina, {Maggy W} and Yuen, {Eunice Y} and Zhen Yan and Goldberg, {Matthew S} and Nairn, {Angus C} and Paul Greengard and Nestler, {Eric J} and Ronald Taussig and Akinori Nishi and Houslay, {Miles D} and Bibb, {James A}",

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Plattner, F, Hayashi, K, Hernández, A, Benavides, DR, Tassin, TC, Tan, C, Day, J, Fina, MW, Yuen, EY, Yan, Z, Goldberg, MS, Nairn, AC, Greengard, P, Nestler, EJ, Taussig, R, Nishi, A, Houslay, MD & Bibb, JA 2015, 'The role of ventral striatal cAMP signaling in stress-induced behaviors', Nature Neuroscience, vol. 18, no. 8, pp. 1094-11100. https://doi.org/10.1038/nn.4066

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AU - Plattner, Florian

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AU - Tan, Chunfeng

AU - Day, Jonathan

AU - Fina, Maggy W

AU - Yuen, Eunice Y

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AU - Goldberg, Matthew S

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AU - Greengard, Paul

AU - Nestler, Eric J

AU - Taussig, Ronald

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AU - Houslay, Miles D

AU - Bibb, James A

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AB - 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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JO - Nature Neuroscience

JF - Nature Neuroscience

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ER -

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

Abstract

Keywords

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