title: Low levels of methyl β-cyclodextrin disrupt GluA1-dependent synaptic potentiation but not synaptic depression.
abstract: Methyl-β-cyclodextrin (MβCD) is a reagent that depletes cholesterol and disrupts lipid rafts, a type of cholesterol-enriched cell membrane microdomain. Lipid rafts are essential for neuronal functions such as synaptic transmission and plasticity, which are sensitive to even low doses of MβCD. However, how MβCD changes synaptic function, such as N-methyl-d-aspartate receptor (NMDA-R) activity, remains unclear. We monitored changes in synaptic transmission and plasticity after disrupting lipid rafts with MβCD. At low concentrations (0.5 mg/mL), MβCD decreased basal synaptic transmission and miniature excitatory post-synaptic current without changing NMDA-R-mediated synaptic transmission and the paired-pulse facilitation ratio. Interestingly, low doses of MβCD failed to deplete cholesterol or affect α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) and NMDA-R levels, while clearly reducing GluA1 levels selectively in the synaptosomal fraction. Low doses of MβCD decreased the inhibitory effects of NASPM, an inhibitor for GluA2-lacking AMPA-R. MβCD successfully decreased NMDA-R-mediated long-term potentiation but did not affect the formation of either NMDA-R-mediated or group I metabotropic glutamate receptor-dependent long-term depression. MβCD inhibited de-depression without affecting de-potentiation. These results suggest that MβCD regulates GluA1-dependent synaptic potentiation but not synaptic depression in a cholesterol-independent manner.
authors.affiliation: Department of Physiology and Dental Research Institute, Seoul National University School of Dentistry, Seoul, Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Choi
authors.forename: Sunmin
authors.initials: S
authors.lastname: Jung
authors.forename: Jihoon
authors.initials: J
authors.lastname: Nah
authors.forename: Hui-Yeon
authors.initials: HY
authors.lastname: Ko
authors.forename: Su-Hyun
authors.initials: SH
authors.lastname: Jo
authors.forename: Gehoon
authors.initials: G
authors.lastname: Chung
authors.forename: Kyungpyo
authors.initials: K
authors.lastname: Park
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Choi
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects; D047392:beta-Cyclodextrins / Q000494:pharmacology*
chemical_list: D002784:Cholesterol; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin
keywords: AMPA receptor; NMDA receptor; lipid rafts; long-term depression; long-term potentiation; methyl-β-cyclodextrin