Critical time window of neuronal cholesterol synthesis during neurite outgrowth.
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.
Department of Neurogenetics, Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany.
Ursula
U
Fünfschilling
Wolf J
WJ
Jockusch
Nandhini
N
Sivakumar
Wiebke
W
Möbius
Kristina
K
Corthals
Sai
S
Li
Susanne
S
Quintes
Younghoon
Y
Kim
Iwan A T
IA
Schaap
Jeong-Seop
JS
Rhee
Klaus-Armin
KA
Nave
Gesine
G
Saher
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000924:Anticholesteremic Agents; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D002784:Cholesterol / Q000096:biosynthesis* / Q000494:pharmacology; D004622:Embryo, Mammalian; D036386:Ephrin-A5 / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009434:Neural Pathways / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000254:growth & development; D016501:Neurites / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016622:Silver Staining; D013997:Time Factors; D014233:Tricarboxylic Acids / Q000494:pharmacology; D047392:beta-Cyclodextrins / Q000494:pharmacology
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D001426:Bacterial Proteins; D051792:Basic Helix-Loop-Helix Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002784:Cholesterol; D036386:Ephrin-A5; D013186:Farnesyl-Diphosphate Farnesyltransferase; D005904:Glial Fibrillary Acidic Protein; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014233:Tricarboxylic Acids; D047392:beta-Cyclodextrins; C110701:Neurod6 protein, mouse; C108732:methyl-beta-cyclodextrin; C054562:yellow fluorescent protein, Bacteria; C075117:squalestatin 1