Induction of neuronal vascular endothelial growth factor expression by cAMP in the dentate gyrus of the hippocampus is required for antidepressant-like behaviors.
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 oa(1)), a G(s)-coupled receptor, is transgenically expressed in the forebrain neurons of mice. Chronic activation of the heterologous Ap oa(1) 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.
Lee
Jeong-Sik
JS
Department of Biochemistry and Molecular Biology, Hanyang University College of Medicine, 133-791 Seoul, Korea.
Jang
Deok-Jin
DJ
Lee
Nuribalhae
N
Ko
Hyoung-Gon
HG
Kim
Hyoung
H
Kim
Yong-Seok
YS
Kim
Byungwoo
B
Son
Junehee
J
Kim
Sung Hyun
SH
Chung
Heekyoung
H
Lee
Mun-Yong
MY
Kim
Woon Ryoung
WR
Sun
Woong
W
Zhuo
Min
M
Abel
Ted
T
Kaang
Bong-Kiun
BK
Son
Hyeon
H
D000704:Analysis of Variance; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D002461:Cell Line, Transformed; D047369:Chromatin Immunoprecipitation / Q000379:methods; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D018891:Dentate Gyrus / Q000166:cytology*; D003863:Depression / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005106:Exploratory Behavior; D005247:Feeding Behavior; D005473:Fluoxetine / Q000494:pharmacology; D005518:Food Preferences / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009655:Octopamine / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D017982:Receptors, Biogenic Amine / Q000235:genetics; D014162:Transfection / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D018687:Antidepressive Agents, Second-Generation; D019208:Brain-Derived Neurotrophic Factor; D034741:RNA, Small Interfering; D017982:Receptors, Biogenic Amine; D042461:Vascular Endothelial Growth Factor A; D014662:Vasoconstrictor Agents; C027604:norsynephrine receptor; D005473:Fluoxetine; D009655:Octopamine; D000242:Cyclic AMP; D050882:CREB-Binding Protein; D001973:Bromodeoxyuridine