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


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.

Download full-text


Available from: Daniela Mauceri, Aug 14, 2014
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Identify genetic factors associated with cognitive maintenance in late life and assess their association with gray matter (GM) volume in brain networks affected in aging. Methods We conducted a genome-wide association study of ∼2.4 M markers to identify modifiers of cognitive trajectories in Caucasian participants (N = 7,328) from two population-based cohorts of non-demented elderly. Standardized measures of global cognitive function (z-scores) over 10 and 6 years were calculated among participants and mixed model regression was used to determine subject-specific cognitive slopes. “Cognitive maintenance” was defined as a change in slope of ≥ 0 and was compared with all cognitive decliners (slope < 0). In an independent cohort of cognitively normal older Caucasians adults (N = 122), top association findings were then used to create genetic scores to assess whether carrying more cognitive maintenance alleles was associated with greater GM volume in specific brain networks using voxel-based morphometry. ResultsThe most significant association was on chromosome 11 (rs7109806, P = 7.8 × 10−8) near RIC3. RIC3 modulates activity of α7 nicotinic acetylcholine receptors, which have been implicated in synaptic plasticity and beta-amyloid binding. In the neuroimaging cohort, carrying more cognitive maintenance alleles was associated with greater volume in the right executive control network (RECN; PFWE = 0.01). Conclusions These findings suggest that there may be genetic loci that promote healthy cognitive aging and that they may do so by conferring robustness to GM in the RECN. Future work is required to validate top candidate genes such as RIC3 for involvement in cognitive maintenance. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    Human Brain Mapping 09/2014; 35(9). DOI:10.1002/hbm.22494 · 5.97 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS) is associated with ectopic lymphoid follicle formation. Podoplanin+ (lymphatic marker) T helper17 (Th17) cells and B cell aggregates have been implicated in the formation of tertiary lymphoid organs (TLOs) in MS and experimental autoimmune encephalitis (EAE). Since podoplanin expressed by Th17 cells in MS brains is also expressed by lymphatic endothelium, we investigated whether the pathophysiology of MS involves inductions of lymphatic proteins in the inflamed neurovasculature. We assessed the protein levels of lymphatic vessel endothelial hyaluronan receptor and podoplanin, which are specific to the lymphatic system and prospero-homeobox protein-1, angiopoietin-2, vascular endothelial growth factor-D, vascular endothelial growth factor receptor-3, which are expressed by both lymphatic endothelium and neurons. Levels of these proteins were measured in postmortem brains and sera from MS patients, in the myelin proteolipid protein (PLP)-induced EAE and Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD) mouse models and in cell culture models of inflamed neurovasculature.Results and conclusions: Intense staining for LYVE-1 was found in neurons of a subset of MS patients using immunohistochemical approaches. The lymphatic protein, podoplanin, was highly expressed in perivascular inflammatory lesions indicating signaling cross-talks between inflamed brain vasculature and lymphatic proteins in MS. The profiles of these proteins in MS patient sera discriminated between relapsing remitting MS from secondary progressive MS and normal patients. The in vivo findings were confirmed in the in vitro cell culture models of neuroinflammation.
    Journal of Neuroinflammation 10/2013; 10(1):125. DOI:10.1186/1742-2094-10-125 · 5.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The author has developed an effective method for modelling very complex systems, called n -port symbolic neural (NPSN) modeling. Both production-rule sets and back-propagation multilayer neural nets are used as building blocks. This method is effective for the development of `trained' models of real physical systems both for simulation of the system as built (with possible faults), and for the modeling of human control behavior. Methods have been devised to speed up the notoriously slow learning process in back-propagation networks. It is shown that if large networks are broken down into architectures of smaller networks to make the input-output data of each subnetwork strictly monotonic, this speeds up the training process. An NPSN model is being created to model the pilot in controlling an airplane in instrument-flying situations. The nature of NPSN models is described, and an example NPSN design cycle is considered
    Systems, Man and Cybernetics, 1989. Conference Proceedings., IEEE International Conference on; 12/1989
Show more