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VEGF links hippocampal activity with neurogenesis, learning and memory

Nature Genetics volume 36, pages 827–835 (2004)Cite this article

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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Figure 1: Screening potential mediators of the effects of experience on hippocampal plasticity.
Figure 2: Transgene expression after intrahippocampal rAAV delivery.
Figure 3: Behavioral phenotype after gene transfer.
Figure 4: Vascular effects after gene transfer.
Figure 5: Neuronal effects after gene transfer
Figure 6: Survival and differentiation of BrdU+ cells 1 month after BrdU injection.
Figure 7: RNAi knockdown of VEGF expression in dorsal hippocampus inhibits enrichment-induced neurogenesis.

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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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Authors and Affiliations

  1. Department of Neurological Surgery, Weill Medical College of Cornell University, New York, 10021, New York, USA

    Lei Cao & Matthew J During

  2. Department of Neurosurgery, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, 19107, Pennsylvania, USA

    Lei Cao, Xiangyang Jiao, David S Zuzga, Yuhong Liu & Matthew J During

  3. Department of Molecular Medicine & Pathology, Laboratory of Functional Genomics and Translational Neuroscience, University of Auckland, Auckland, New Zealand

    Dahna M Fong, Deborah Young & Matthew J During

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Correspondence to Matthew J During.

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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)

Supplementary Methods (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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