Nature Genetics36, 827 - 835 (2004)
Published online: 18 July 2004; | doi:10.1038/ng1395
VEGF links hippocampal activity with neurogenesis, learning and memory
Lei Cao1, 2, Xiangyang Jiao2, David S Zuzga2, Yuhong Liu2, Dahna M Fong3, Deborah Young3
& Matthew J During1, 2, 3
1
Department of Neurological Surgery, Weill Medical College of Cornell University, New York, New York 10021, USA.
2
Department of Neurosurgery, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, USA
3
Laboratory of Functional Genomics and Translational Neuroscience, Department of Molecular Medicine & Pathology, University of Auckland, Auckland, New Zealand.
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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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.
