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The Journal of Neuroscience, July 1, 2009, 29(26):8493-8505; doi:10.1523/JNEUROSCI.1321-09.2009

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Behavioral/Systems/Cognitive
Induction of Neuronal Vascular Endothelial Growth Factor Expression by cAMP in the Dentate Gyrus of the Hippocampus Is Required for Antidepressant-Like Behaviors

Jeong-Sik Lee,¹ Deok-Jin Jang,³ Nuribalhae Lee,³ Hyoung-Gon Ko,³ Hyoung Kim,³ Yong-Seok Kim,¹ Byungwoo Kim,¹ Junehee Son,³ Sung Hyun Kim,¹ Heekyoung Chung,² Mun-Yong Lee,⁴ Woon Ryoung Kim,⁵ Woong Sun,⁵ Min Zhuo,⁶ Ted Abel,⁷ Bong-Kiun Kaang,³ and Hyeon Son¹

Departments of ¹Biochemistry and Molecular Biology and ²Pathology, Hanyang University College of Medicine, 133-791 Seoul, Korea, ³School of Biological Sciences, College of Natural Sciences, Seoul National University, 151-742 Seoul, Korea, ⁴Department of Anatomy, College of Medicine, The Catholic University of Korea, 137-701 Seoul, Korea, ⁵Department of Anatomy, Korea University College of Medicine, 136-701 Seoul, Korea, ⁶Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and ⁷Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Hyeon Son at the above address. Email: hyeonson{at}hanyang.ac.kr

The cAMP cascade and vascular endothelial growth factor (VEGF) are critical modulators of depression. Here we have tested whether the antidepressive effect of the cAMP cascade is mediated by VEGF in the adult hippocampus. We used a conditional genetic system in which the Aplysia octopamine receptor (Ap oa₁), a G_s-coupled receptor, is transgenically expressed in the forebrain neurons of mice. Chronic activation of the heterologous Ap oa₁ by its natural ligand evoked antidepressant-like behaviors, accompanied by enhanced phosphorylation of cAMP response element-binding protein and transcription of VEGF in hippocampal dentate gyrus (DG) neurons. Selective knockdown of VEGF in these cells during the period of cAMP elevation inhibited the antidepressant-like behaviors. These findings reveal a molecular interaction between the cAMP cascade and VEGF expression, and the pronounced behavioral consequences of this interaction shed light on the mechanism underlying neuronal VEGF functions in antidepression.

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Received March 18, 2009; revised May 7, 2009; accepted May 26, 2009.

Correspondence should be addressed to Hyeon Son at the above address. Email: hyeonson{at}hanyang.ac.kr

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