Biomedical subjects

Christiaan N Levelt

Publications and source records attributed to Christiaan N Levelt.

4 recordsLinked to original sources

PubMed2006

Postsynaptic TrkB signaling has distinct roles in spine maintenance in adult visual cortex and hippocampus.

In adult primary visual cortex (V1), dendritic spines are more persistent than during development. Brain-derived neurotrophic factor (BDNF) increases synaptic strength, and its levels rise during cortical development. We therefore asked whether postsynaptic BDNF signaling through its receptor TrkB regulates spine persistence in adult V1. This question has been difficult to address because most methods used to alter TrkB signaling in vivo affect cortical development or cannot distinguish between pre- and postsynaptic mechanisms. We circumvented these problems by employing transgenic mice expressing a dominant negative TrkB-EGFP fusion protein in sparse pyramidal neurons of the adult neocortex and hippocampus, producing a Golgi-staining-like pattern. In adult V1, expression of dominant negative TrkB-EGFP resulted in reduced mushroom spine maintenance and synaptic efficacy, accompanied by an increase in long and thin spines and filopodia. In contrast, mushroom spine maintenance was unaffected in CA1, indicating that TrkB plays fundamentally different roles in structural plasticity in these brain areas.

Animals↗

PubMed2005

Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a heritable disorder of connective tissue, affecting mainly skin, eye and the cardiovascular system. PXE is characterized by dystrophic mineralization of elastic fibres. The condition is caused by loss of function mutations in ABCC6. We generated Abcc6 deficient mice (Abcc6-/-) by conventional gene targeting. As shown by light and electron microscopy Abcc6-/- mice spontaneously developed calcification of elastic fibres in blood vessel walls and in Bruch's membrane in the eye. No clear abnormalities were seen in the dermal extracellular matrix. Calcification of blood vessels was most prominent in small arteries in the cortex of the kidney, but in old mice, it occurred also in other organs and in the aorta and vena cava. Newly developed monoclonal antibodies against mouse Abcc6 localized the protein to the basolateral membranes of hepatocytes and the basal membrane in renal proximal tubules, but failed to show the protein at the pathogenic sites. Abcc6-/- mice developed a 25% reduction in plasma HDL cholesterol and an increase in plasma creatinine levels, which may be due to impaired kidney function. No changes in serum mineral balance were found. We conclude that the phenotype of the Abcc6-/- mouse shares calcification of elastic fibres with human PXE pathology, which makes this model a useful tool to further investigate the aetiology of PXE. Our data support the hypothesis that PXE is in fact a systemic disease.

ATP-Binding Cassette Transporters↗

PubMed2005

Structural plasticity in the developing visual system.

The visual system has been used extensively to study cortical plasticity during development. Seminal experiments by Hubel and Wiesel (Wiesel, T.N. and Hubel, D.H. (1963) Single cell responses in striate cortex of kittens deprived of vision in one eye. J. Neurophysiol., 26: 1003-1017.) identified the visual cortex as a very attractive model for studying structural and functional plasticity regulated by experience. It was discovered that the thalamic projections to the visual cortex, and neuronal connectivity in the visual cortex itself, were organized in alternating columns dominated by input from the left or the right eye. This organization was shown to be strongly influenced by manipulating binocular input during a specific time point of postnatal development known as the critical period. Two chapters in this volume review the molecular and functional aspects of this form of plasticity. This chapter reviews the structural changes that occur during ocular dominance (OD) plasticity and their possible functional relevance, and discusses developments in the methods that allow the analysis of the molecular and cellular mechanisms that regulate them.

Animals↗

PubMed2005

Activation of the Notch pathway in Down syndrome: cross-talk of Notch and APP.

Down syndrome (DS) patients suffer from mental retardation, but also display enhanced beta-APP production and develop cortical amyloid plaques at an early age. As beta-APP and Notch are both processed by gamma-secretase, we analyzed expression of the Notch signaling pathway in the adult DS brain and in a model system for DS, human trisomy 21 fibroblasts by quantitative PCR. In adult DS cortex we found that Notch1, Dll1 and Hes1 expression is up-regulated. Moreover, DS fibroblasts and Alzheimer disease cortex also show overexpression of Notch1 and Dll1, indicating that enhanced beta-APP processing found in both DS and AD could be instrumental in these changes. Using pull-down studies we could demonstrate interaction of APP with Notch1, suggesting that these transmembrane proteins form heterodimers, but independent of gamma-secretase. We could demonstrate binding of the intracellular domain of Notch1 to the APP adaptor protein Fe65. Furthermore, activated Notch1 can trans-activate an APP target gene, Kai1, and vice versa, activated APP can trans-activate the classical Notch target gene Hes1. These data suggest that Notch expression is activated in Down syndrome, possibly through cross-talk with APP signaling. This interaction might affect brain development, since the Notch pathway plays a pivotal role in neuron-glia differentiation.

Adult↗