Critical time window of neuronal cholesterol synthesis during neurite outgrowth
(2012) In The Journal of Neuroscience : the official journal of the Society for Neuroscience 32(22). p.45-7632- 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... (More)
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.
(Less)
- author
- publishing date
- 2012-05-30
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Analysis of Variance, Animals, Animals, Newborn, Anticholesteremic Agents, Apolipoproteins E/genetics, Bacterial Proteins/genetics, Basic Helix-Loop-Helix Transcription Factors/genetics, Bridged Bicyclo Compounds, Heterocyclic/pharmacology, Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics, Cell Differentiation/drug effects, Cell Survival/drug effects, Cells, Cultured, Cerebral Cortex/cytology, Cholesterol/biosynthesis, Embryo, Mammalian, Ephrin-A5/pharmacology, Excitatory Postsynaptic Potentials/drug effects, Farnesyl-Diphosphate Farnesyltransferase/genetics, Gene Expression Regulation, Developmental/genetics, Glial Fibrillary Acidic Protein/metabolism, Growth Cones/drug effects, Hippocampus/cytology, Humans, Luminescent Proteins/genetics, Mice, Mice, Transgenic, Microglia/drug effects, Mutation/genetics, Nerve Tissue Proteins/genetics, Neural Pathways/cytology, Neurites/drug effects, Neurons/cytology, Patch-Clamp Techniques, RNA, Messenger/metabolism, Signal Transduction/drug effects, Silver Staining, Time Factors, Tricarboxylic Acids/pharmacology, beta-Cyclodextrins/pharmacology
- in
- The Journal of Neuroscience : the official journal of the Society for Neuroscience
- volume
- 32
- issue
- 22
- pages
- 45 - 7632
- publisher
- Society for Neuroscience
- external identifiers
-
- pmid:22649242
- scopus:84861582724
- ISSN
- 1529-2401
- DOI
- 10.1523/JNEUROSCI.1352-11.2012
- language
- English
- LU publication?
- no
- id
- 9c98ff3f-174e-4da6-93ac-726bd7368ab8
- date added to LUP
- 2024-09-04 11:24:53
- date last changed
- 2024-11-28 14:32:54
@article{9c98ff3f-174e-4da6-93ac-726bd7368ab8,
abstract = {{<p>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.</p>}},
author = {{Fünfschilling, Ursula and Jockusch, Wolf J and Sivakumar, Nandhini and Möbius, Wiebke and Corthals, Kristina and Li, Sai and Quintes, Susanne and Kim, Younghoon and Schaap, Iwan A T and Rhee, Jeong-Seop and Nave, Klaus-Armin and Saher, Gesine}},
issn = {{1529-2401}},
keywords = {{Analysis of Variance; Animals; Animals, Newborn; Anticholesteremic Agents; Apolipoproteins E/genetics; Bacterial Proteins/genetics; Basic Helix-Loop-Helix Transcription Factors/genetics; Bridged Bicyclo Compounds, Heterocyclic/pharmacology; Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics; Cell Differentiation/drug effects; Cell Survival/drug effects; Cells, Cultured; Cerebral Cortex/cytology; Cholesterol/biosynthesis; Embryo, Mammalian; Ephrin-A5/pharmacology; Excitatory Postsynaptic Potentials/drug effects; Farnesyl-Diphosphate Farnesyltransferase/genetics; Gene Expression Regulation, Developmental/genetics; Glial Fibrillary Acidic Protein/metabolism; Growth Cones/drug effects; Hippocampus/cytology; Humans; Luminescent Proteins/genetics; Mice; Mice, Transgenic; Microglia/drug effects; Mutation/genetics; Nerve Tissue Proteins/genetics; Neural Pathways/cytology; Neurites/drug effects; Neurons/cytology; Patch-Clamp Techniques; RNA, Messenger/metabolism; Signal Transduction/drug effects; Silver Staining; Time Factors; Tricarboxylic Acids/pharmacology; beta-Cyclodextrins/pharmacology}},
language = {{eng}},
month = {{05}},
number = {{22}},
pages = {{45--7632}},
publisher = {{Society for Neuroscience}},
series = {{The Journal of Neuroscience : the official journal of the Society for Neuroscience}},
title = {{Critical time window of neuronal cholesterol synthesis during neurite outgrowth}},
url = {{http://dx.doi.org/10.1523/JNEUROSCI.1352-11.2012}},
doi = {{10.1523/JNEUROSCI.1352-11.2012}},
volume = {{32}},
year = {{2012}},
}