VEGF links hippocampal activity with neurogenesis, learning and memory

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 approximately 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.

Upregulation of Flk-1 by bFGF via the ERK pathway is essential for VEGF-mediated promotion of neural stem cell proliferation

“…In most occasions, VEGF exerts its action via its receptor, Flk-1, in endothelial cells, hematopoietic stem/progenitor cells and some tumor cells [11][12][13][14]. In the central nervous system (CNS), for instance the hippocampus, VEGF stimulates the expansion of NSCs and neurogenesis in various animal models, resulting in improved learning ability [15][16][17][18]. In adults, NSCs are found in close proximity to blood vessels and surrounded by glial cells in the hippocampus and the subventricular zone.…”

Adult Neurogenesis and Hippocampal Memory Function: New Cells, More Plasticity, New Memories?

“…Overexpression of vascular endothelial growth factor (VEGF) in the hippocampus using recombinant adenoassociated viral vectors led to a twofold increase in neurogenesis, and inhibition of VEGF expression by RNA interference completely blocked the environmental induction of neurogenesis [70]. This animal model of VEGF overexpression also showed a positive correlation between increases in adult neurogenesis and improved cognitive function in the water maze and passive avoidance tasks [70]. In another example, deletion of methyl-CpG binding protein 1 (MBD1), a member of the methylated DNA-binding protein family, increased genomic instability in adult NSCs and caused a reduction in hippocampal DG neurogenesis.…”

AAV vectors for RNA-based modulation of gene expression

“…22,23 Hippocampal neurogenesis can be induced by housing adult rats in an 'enriched' environment. Using AAV vectors, Cao et al 24 have obtained evidence that this neural remodelling process is mediated by vascular endothelial growth factor. An AAV vector carrying an shRNA against vascular endothelial growth factor was packaged with a mixture of AAV1 and AAV2 capsid proteins and injected into the dorsal hippocampus of adult rats.…”

“…The injected animals were significantly less responsive to the enriched environment than the controls, and displayed reduced neurogenesis, as measured by 5-bromo-2-deoxyuridine incorporation in the dentate gyrus. 24 In another study, the local reduction of calcium/calmodulin-dependent protein kinase II in the hippocampus of rats was achieved following injection of an AAV2/1 vector with a U6-shRNA cassette. Behavioural testing indicated a significant impairment in place learning and changes in exploratory behaviour.…”