Critical Time Window of Neuronal Cholesterol Synthesis during Neurite Outgrowth

Ursula Fuenfschilling, Wolf J. Jockusch, Nandhini Sivakumar, Wiebke Moebius, Kristina Corthals, Sai Li, Susanne Quintes, Younghoon Kim, Iwan A. T. Schaap, Jeong-Seop Rhee, Klaus-Armin Nave, Gesine Saher

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Cholesterol is an essential membrane component enriched in plasma membranes, growth cones, and synapses. The brain normally synthesizes all cholesterol locally, but the contribution of individual cell types to brain cholesterol metabolism is unknown. To investigate whether cortical projection neurons in vivo essentially require cholesterol biosynthesis and which cell types support neurons, we have conditionally ablated the cholesterol biosynthesis in these neurons in mice either embryonically or postnatally. We found that cortical projection neurons synthesize cholesterol during their entire lifetime. At all stages, they can also benefit from glial support. Adult neurons that lack cholesterol biosynthesis are mainly supported by astrocytes such that their functional integrity is preserved. In contrast, microglial cells support young neurons. However, compensatory efforts of microglia are only transient leading to layer-specific neuronal death and the reduction of cortical projections. Hence, during the phase of maximal membrane growth and maximal cholesterol demand, neuronal cholesterol biosynthesis is indispensable. Analysis of primary neurons revealed that neurons tolerate only slight alteration in the cholesterol content and plasma membrane tension. This quality control allows neurons to differentiate normally and adjusts the extent of neurite outgrowth, the number of functional growth cones and synapses to the available cholesterol. This study highlights both the flexibility and the limits of horizontal cholesterol transfer in vivo and may have implications for the understanding of neurodegenerative diseases.

Original languageEnglish
Pages (from-to)7632-7645
Number of pages14
JournalJournal of Neuroscience
Volume32
Issue number22
DOIs
Publication statusPublished - 30 May 2012

Keywords

  • CENTRAL-NERVOUS-SYSTEM
  • HIPPOCAMPAL-NEURONS
  • LIPID RAFTS
  • CNS SYNAPTOGENESIS
  • TRKB RECEPTORS
  • CELL-DEATH
  • IN-VIVO
  • LOCALIZATION
  • ACTIVATION
  • SUBTYPE

Cite this

Fuenfschilling, U., Jockusch, W. J., Sivakumar, N., Moebius, W., Corthals, K., Li, S., Quintes, S., Kim, Y., Schaap, I. A. T., Rhee, J-S., Nave, K-A., & Saher, G. (2012). Critical Time Window of Neuronal Cholesterol Synthesis during Neurite Outgrowth. Journal of Neuroscience, 32(22), 7632-7645. https://doi.org/10.1523/JNEUROSCI.1352-11.2012