Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability.
Cholesterol/sphingolipid microdomains (lipid rafts) in the membrane are involved in protein trafficking, formation of signaling complexes, and regulation of actin cytoskeleton. Here, we show that lipid rafts exist abundantly in dendrites of cultured hippocampal neurons, in which they are associated with several postsynaptic proteins including surface AMPA receptors. Depletion of cholesterol/sphingolipid leads to instability of surface AMPA receptors and gradual loss of synapses (both inhibitory and excitatory) and dendritic spines. The remaining synapses and spines in raft-depleted neurons become greatly enlarged. The importance of lipid rafts for normal synapse density and morphology could explain why cholesterol promotes synapse maturation in retinal ganglion cells (Mauch et al., 2001) and offers a potential link between disordered cholesterol metabolism and the synapse loss seen in neurodegenerative disease.
Hering
Heike
H
Picower Center for Learning and Memory, Howard Hughes Medical Institute, and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Lin
Chih-Chun
CC
Sheng
Morgan
M
D000818:Animals; D001923:Brain Chemistry; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry; D002478:Cells, Cultured; D002784:Cholesterol / Q000032:analysis; D003712:Dendrites / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D003902:Detergents / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005372:Filipin / Q000737:chemistry / Q000378:metabolism; D037341:Fumonisins / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D021962:Membrane Microdomains / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D009474:Neurons / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis; D013107:Sphingolipids / Q000032:analysis; D013347:Subcellular Fractions / Q000737:chemistry; D013569:Synapses / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
D002352:Carrier Proteins; D003902:Detergents; D004791:Enzyme Inhibitors; D037341:Fumonisins; C491308:Grip1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; C409466:NR1 NMDA receptor; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013107:Sphingolipids; C033652:postsynaptic density proteins; C012258:mevastatin; C056933:fumonisin B1; D005372:Filipin; D002784:Cholesterol; D008148:Lovastatin