Abstract
The cholesterol chelating agent, methyl-β-cyclodextrin (MβCD), alters synaptic function in many systems. At crayfish neuromuscular junctions, MβCD 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 MβCD correlate with its ability to reduce cholesterol, and used thermal acclimatization as an alternative method to modify cholesterol levels. MβCD impaired impulse propagation and decreased EJP amplitude by 40% (P<0.05) in preparations from crayfish acclimatized to 14°C but not from those acclimatized to 21°C. The reduction in EJP amplitude in the cold-acclimatized group was associated with a 49% reduction in quantal content (P<0.05). MβCD 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). MβCD 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 MβCD 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 MβCD can affect both presynaptic and postsynaptic properties, and that some effects of MβCD are unrelated to cholesterol chelation.
Highlights
Cholesterol is an intriguing molecule linked to numerous fundamental physiological functions; alterations in cholesterol metabolism are associated with a range of disorders that include significant current and future healthcare burdens [1,2]
Effects of MbCD on synaptic transmission Effects of the cholesterol chelator, methyl-b-cyclodextrin (MbCD), on neuromuscular synapses were first assessed by recording excitatory junctional potentials (EJPs) in phasic abdominal extensor muscles (Fig. 1)
At the stimulus frequency used (0.2 Hz) there was a gradual decrease in EJP amplitude over several minutes, due to low frequency depression [12,32]; such depression was present in preparations from both cold- and warmacclimatized crayfish and was modest, decreasing EJP amplitude by,20–30% during the 40 min over which recordings were made Fig. 2A–B)
Summary
Cholesterol is an intriguing molecule linked to numerous fundamental physiological functions; alterations in cholesterol metabolism are associated with a range of disorders that include significant current and future healthcare burdens [1,2]. Studies utilizing MbCD have implicated cholesterol in mediating or modulating a wide range of membrane-associated cell properties and functions in a range of secretory cell types, including neurons. Such cellular processes include excitability [11,12,13,14], ion channel activity [15,16], exocytosis [3,4,17,18,19], endocytosis / vesicle recycling [20,21], neurotransmitter uptake and storage [22,23] and postsynaptic receptor localization [16,24,25,26]. Such studies make a case that cholesterol may be a critical membrane component for all the key steps in chemical synaptic transmission
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