Cholesterol-Independent Effects of Methyl-β-Cyclodextrin on Chemical Synapses

The cholesterol chelating agent, methyl-beta-cyclodextrin (M beta CD), alters synaptic function in many systems. At crayfish neuromuscular junctions, M beta CD is reported to reduce excitatory junctional potentials (EJPs) by impairing impulse propagation to synaptic terminals, and to have no postsynaptic effects. We examined the degree to which physiological effects of M beta CD correlate with its ability to reduce cholesterol, and used thermal acclimatization as an alternative method to modify cholesterol levels. M beta CD impaired impulse propagation and decreased EJP amplitude by 40% (P < 0.05) in preparations from crayfish acclimatized to 14 degrees C but not from those acclimatized to 21 degrees C. The reduction in EJP amplitude in the cold-acclimatized group was associated with a 49% reduction in quantal content (P < 0.05). M beta CD had no effect on input resistance in muscle fibers but decreased sensitivity to the neurotransmitter L-glutamate in both warm- and cold-acclimatized groups. This effect was less pronounced and reversible in the warm-acclimatized group (90% reduction in cold, P < 0.05; 50% reduction in warm, P < 0.05). M beta CD reduced cholesterol in isolated nerve and muscle from cold- and warm-acclimatized groups by comparable amounts (nerve: 29% cold, 25% warm; muscle: 20% cold, 18% warm; P < 0.05). This effect was reversed by cholesterol loading, but only in the warm-acclimatized group. Thus, effects of M beta CD on glutamate-sensitivity correlated with its ability to reduce cholesterol, but effects on impulse propagation and resulting EJP amplitude did not. Our results indicate that M beta CD can affect both presynaptic and postsynaptic properties, and that some effects of M beta CD are unrelated to cholesterol chelation.