Cholesterol and lipid microdomains stabilize the postsynapse at the neuromuscula

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EMBO J. 2006 Aug 24

Cholesterol and lipid microdomains stabilize the postsynapse at the

neuromuscular junction.

Willmann R, Pun S, Stallmach L, Sadasivam G, Santos AF, Caroni P,

Fuhrer C.

Department of Neurochemistry, Brain Research Institute, University of

Zurich, Zurich, Switzerland.

Stabilization and maturation of synapses are important for

development and function of the nervous system. Previous studies have

implicated cholesterol-rich lipid microdomains in synapse

stabilization, but the underlying mechanisms remain unclear. We found

that cholesterol stabilizes clusters of synaptic acetylcholine

receptors (AChRs) in denervated muscle in vivo and in nerve-muscle

explants. In paralyzed muscles, cholesterol triggered maturation of

nerve sprout-induced AChR clusters into pretzel shape. Cholesterol

treatment also rescued a specific defect in AChR cluster stability in

cultured src(-/-);fyn(-/-) myotubes. Postsynaptic proteins including

AChRs, rapsyn, MuSK and Src-family kinases were strongly enriched in

lipid microdomains prepared from wild-type myotubes. Microdomain

disruption by cholesterol-sequestering methyl-beta-cyclodextrin

disassembled AChR clusters and decreased AChR-rapsyn interaction and

AChR phosphorylation. Amounts of microdomains and enrichment of

postsynaptic proteins into microdomains were decreased in src(-/-);fyn

(-/-) myotubes but rescued by cholesterol treatment. These data

provide evidence that cholesterol-rich lipid microdomains and SFKs

act in a dual mechanism in stabilizing the postsynapse: SFKs enhance

microdomain-association of postsynaptic components, whereas

microdomains provide the environment for SFKs to maintain

interactions and phosphorylation of these components.