Abstract
An enriched environment is associated with hippocampal plasticity, including improved cognitive performance and increased neurogenesis. Here, we show that hippocampal expression of vascular endothelial growth factor (VEGF) is increased by both an enriched environment and performance in a spatial maze. Hippocampal gene transfer of VEGF in adult rats resulted in ∼2 times more neurogenesis associated with improved cognition. In contrast, overexpression of placental growth factor, which signals through Flt1 but not kinase insert domain protein receptors (KDRs), had negative effects on neurogenesis and inhibited learning, although it similarly increased endothelial cell proliferation. Expression of a dominant-negative mutant KDR inhibited basal neurogenesis and impaired learning. Coexpression of mutant KDR antagonized VEGF-enhanced neurogenesis and learning without inhibiting endothelial cell proliferation. Furthermore, inhibition of VEGF expression by RNA interference completely blocked the environmental induction of neurogenesis. These data support a model in which VEGF, acting through KDR, mediates the effect of the environment on neurogenesis and cognition.
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Acknowledgements
We thank C. Croce for use of his laboratory facilities; R.G. Morris and C. Haile for discussions and advice regarding behavioral experiments; P. Lawlor for help with shRNA vector packaging; R. Horst, C. Leichtlein, B. Klaussner for technical assistance; R. Bland for critical reading of the manuscript; and the New Zealand Health Research Council for research support. D.Y. was supported by a Health Research Council Sir Charles Hercus Health Research Fellowship.
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Supplementary information
Supplementary Fig. 1
Western blot of Phospho KDR in dorsal hippocampus after gene transfer. (PDF 39 kb)
Supplementary Fig. 2
Dominant negative KDR expression downregulated phospho-ERK1/ERK2 in hippocampus. (PDF 14 kb)
Supplementary Fig. 3
Screening antibodies to human VEGF and AAV2 using ELISA. (PDF 30 kb)
Supplementary Table 1
Human VEGF and PGF overexpression downregulated endogenous rat Vegfa mRNA. (PDF 5 kb)
Supplementary Table 2
Blood-brain barrier permeability to Evan's blue after unilateral injection of AAV vectors. (PDF 6 kb)
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Cao, L., Jiao, X., Zuzga, D. et al. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 36, 827–835 (2004). https://doi.org/10.1038/ng1395
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DOI: https://doi.org/10.1038/ng1395
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