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The role of cholesterol in neuronal development and function

Antragstellerin Dr. Gesine Saher
Fachliche Zuordnung Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Förderung Förderung von 2010 bis 2015
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 171963272
 
Erstellungsjahr 2015

Zusammenfassung der Projektergebnisse

Cholesterol is an essential component of the plasma membrane and its proper localization and enrichment in lipid rafts, growth cones and synapses is important for neuronal function. Since nutritional cholesterol cannot enter the CNS under physiological conditions, neural cells produce cholesterol locally. Using genetic tools we have conditionally ablated cholesterol biosynthesis in forebrain projection neurons in mice either during embryonic development or postnatally. We found that upon postnatal ablation of cholesterol synthesis, functional integrity of mutant neurons is preserved likely by increase of horizontal cholesterol transfer via lipoproteins originating from astrocytes. However, developmental targeting of cholesterol synthesis resulted in layer-specific neuronal death and reduction of cortical projections despite evident microglial support. In vitro studies of primary mutant neurons revealed reduced neurite number and length, less (but functional) growth cones and fewer (but functional) synapses. All of these changes were rescued in vitro by supplemented cholesterol. Together, these data imply a quality control that allows neurons to differentiate normally and to adjust the extent of neurite outgrowth, the number of functional growth cones and synapses to the available cholesterol. Our findings illustrate the flexibility and the limits of horizontal cholesterol transfer in vivo and demonstrate a critical time window during development in which neuronal cholesterol synthesis is indispensable.

Projektbezogene Publikationen (Auswahl)

 
 

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