Vascular endothelial growth factor-dependent spinogenesis underlies antidepressant-like effects of enriched environment.
Current antidepressant treatments remain limited by poor efficacy and a slow onset of action. Increasing evidence demonstrates that enriched environment (EE) treatment can promote structural and behavioral plasticity in the brain and dampen stress-induced alterations of neuroplasticity. Here, we have examined whether short term exposure to EE is able to produce antidepressant-like effects. Our results show that housing adult mice in an EE cage for 7 days led to antidepressant-like behavioral profiles and a significant increase in the number of dendritic spines in hippocampal CA1 pyramidal neurons. These EE-induced antidepressant-like effects are primarily attributed to increased vascular endothelial growth factor (VEGF) expression through a hypoxia-inducible factor-1α (HIF-1α)-mediated transcriptional mechanism. Blockade of HIF-1α synthesis by lentiviral infection with HIF-1α small hairpin RNAs completely blocked the increase in expression of VEGF and the antidepressant-like effects induced by EE. Moreover, no significant antidepressant-like effects were observed with EE treatment in VEGF receptor 2 (Flk-1) knock-out mice. The increase in HIF-1α expression in the hippocampus induced by EE was associated with a decrease in endogenous levels of microRNA-107 (miR-107). Overexpression of miR-107 in the hippocampus completely blocked EE-induced HIF-1α expression and the antidepressant-like effects. These results support a model in which the down-regulation of miR-107, acting through HIF-1α, mediates VEGF-dependent spinogenesis to underlie the EE-induced antidepressant-like effects.
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
Yu-Fei
YF
Huang
Chih-Hao
CH
Yang
Chiung-Chun
CC
Huang
Kuei-Sen
KS
Hsu
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism / Q000502:physiology*; D003345:Corticosterone / Q000378:metabolism; D004777:Environment; D006056:Golgi Apparatus / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D000928:Antidepressive Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C555365:MIRN107 microRNA, mouse; D035683:MicroRNAs; D042461:Vascular Endothelial Growth Factor A; D003345:Corticosterone