Article

Nuclear Calcium-VEGFD Signaling Controls Maintenance of Dendrite Arborization Necessary for Memory Formation

Department of Neurobiology, Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, INF 364, 69120 Heidelberg, Germany.
Neuron (Impact Factor: 15.05). 07/2011; 71(1):117-30. DOI: 10.1016/j.neuron.2011.04.022
Source: PubMed

ABSTRACT

The role of neuronal dendrites is to receive and process synaptic inputs. The geometry of the dendritic arbor can undergo neuronal activity-dependent changes that may impact the cognitive abilities of the organism. Here we show that vascular endothelial growth factor D (VEGFD), commonly known as an angiogenic mitogen, controls the total length and complexity of dendrites both in cultured hippocampal neurons and in the adult mouse hippocampus. VEGFD expression is dependent upon basal neuronal activity and requires nuclear calcium-calmodulin-dependent protein kinase IV (CaMKIV) signaling. Suppression of VEGFD expression in the mouse hippocampus by RNA interference causes memory impairments. Thus, nuclear calcium-VEGFD signaling mediates the effect of neuronal activity on the maintenance of dendritic arbors in the adult hippocampus and is required for cognitive functioning. These results suggest that caution be employed in the clinical use of blockers of VEGFD signaling for antiangiogenic cancer therapy.

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    • "We thus investigated whether depolarizing stimuli could rescue the dendritic phenotype of Lmnb1Δ/Δ neurons. We treated cortical neurons with or without KCl or forskolin, which induce depolarization through distinct mechanisms: calcium and cAMP elevation, respectively (Impey et al., 1998; Wayman et al., 2006; Mauceri et al., 2011). We started treatment from 5 DIV, a critical time for dendrite elongation and branching (Wayman et al., 2006) and measured the length of dendrites and axons 72 h later. "
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    • "Although significant research has gone into understanding the risk factors and pathological processes of dementias , little is known about factors contributing to cognitive maintenance throughout aging. It has been suggested that maintenance of cognitive ability over time involves adaptive changes that compensate for deficits such as reduced synaptic plasticity [Blau et al., 2011], which naturally occur with aging [Mauceri et al., 2011; Raz and Rodrigue, 2006]. "
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    • "Furthermore, VEGF-D plays an important role in neuronal synaptic activity, dendritic length, and in the maintenance of complex dendrite arborization via calcium dependent calcium-calmodulin-dependent protein kinase IV signaling [40]. Inhibition of mouse hippocampal VEGF-D result in memory deficits indicating that calcium dependent VEGF-D signaling is highly important for neuronal function and cognition [40]. Apart from its role in vasculature Ang-2 was also shown to be involved in the regulation of cortical neurogenesis in the telencephelon [39]. "
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