The role of cholesterol in neuronal development and function
Final Report Abstract
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.
Publications
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“Critical time window of neuronal cholesterol synthesis during neurite outgrowth”. J Neurosci 32: 7632-45, 2012
Fünfschilling U, Jockusch WJ, Sivakumar N, Möbius W, Corthals K, Li S, Quintes S, Kim Y, Schaap IAT, Rhee JS, Nave KA, Saher G
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“Cholesterol in myelin biogenesis and hypomyelinating disorders”. Biochimica et Biophysica Acta, 2015 Aug;1851(8):1083-94
Saher G. and Sina Kristin Stumpf
