Cholesterol-dependent balance between evoked and spontaneous synaptic vesicle recycling.
Cholesterol is a prominent component of nerve terminals. To examine cholesterol's role in central neurotransmission, we treated hippocampal cultures with methyl-beta-cyclodextrin, which reversibly binds cholesterol, or mevastatin, an inhibitor of cholesterol biosynthesis, to deplete cholesterol. We also used hippocampal cultures from Niemann-Pick type C1-deficient mice defective in intracellular cholesterol trafficking. These conditions revealed an augmentation in spontaneous neurotransmission detected electrically and an increase in spontaneous vesicle endocytosis judged by horseradish peroxidase uptake after cholesterol depletion by methyl-beta-cyclodextrin. In contrast, responses evoked by action potentials and hypertonicity were severely impaired after the same treatments. The increase in spontaneous vesicle recycling and the decrease in evoked neurotransmission were reversible upon cholesterol addition. Cholesterol removal did not impact on the low level of evoked neurotransmission seen in the absence of synaptic vesicle SNARE protein synaptobrevin-2 whereas the increase in spontaneous fusion remained. These results suggest that synaptic cholesterol balances evoked and spontaneous neurotransmission by hindering spontaneous synaptic vesicle turnover and sustaining evoked exo-endocytosis.
Wasser
Catherine R
CR
Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9111, USA.
Ertunc
Mert
M
Liu
Xinran
X
Kavalali
Ege T
ET
D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000502:physiology*; D004195:Disease Models, Animal; D005071:Evoked Potentials / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000502:physiology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000503:physiopathology; D011506:Proteins / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000502:physiology; D013572:Synaptic Vesicles / Q000502:physiology*; D050988:Vesicle-Associated Membrane Protein 2 / Q000502:physiology; D047392:beta-Cyclodextrins / Q000494:pharmacology
D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D050988:Vesicle-Associated Membrane Protein 2; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C012258:mevastatin; D002784:Cholesterol; D008148:Lovastatin