VEGFD regulation and function in the brain: Focus on neuroprotective activity against stroke-induced dendrite pathology.

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Vascular Endothelial Growth Factor D (VEGFD) is a newly identified regulator of neuronal morphology and cognitive abilities in the adult mouse brain (Mauceri et al., 2011). It is a target of the synaptic NMDA receptor-nuclear calcium signaling pathway and mediates the effects of neuronal activity on the maintenance of dendrite arborization that is required for memory formation. The role of neuronal dendrites is to receive and process synaptic inputs. Changes in the geometry of the dendritic arbor, such as a reduction in length or simplification of the branching patterns, may impact on the cognitive performances of the organism. Indeed, structural alterations of the dendrites have been observed in several neurological disorders with mental inabilities, including Down syndrome and Alzheimers disease; they are also associated with excitotoxicity following a stroke and excessive synaptic activity during seizures. Our recent unpublished results indicate that the stimulation of extrasynaptic NMDA receptors, which are key initiators of cell death pathway in excitotoxicity and also in other neurodegenerative conditions (Hardingham and Bading, 2010), causes a dramatic reduction in VEGFD expression. This suggests a possible causal link between stroke-induced dendrite alterations and the acute loss of VEGFD function. Here we propose to investigate the mechanism through which extrasynaptic NMDA receptor activation by hypoxic-ischemic conditions cause a shut-off of VEGFD expression. We will use an in vitro hippocampal cell culture model for oxygen-glucose deprivation as well as an in vivo mouse stroke model to analyze changes in VEGFD expression, characterize the signaling pathways involved, and monitor, in parallel, morphological alterations of the dendrites. Finally, we will investigate the therapeutic potential of VEGFD and short VEGFD peptide mimetics in protecting against stroke-induced neuronal damage and in facilitating functional recoveries.