Abstract
Cholesterol is a structural component of cellular membranes particularly enriched in synapses but its role in synaptic transmission remains poorly understood. We used rat hippocampal cultures and their acute cholesterol depletion by methyl-β-cyclodextrin as a tool to describe the physiological role of cholesterol in glutamatergic synaptic transmission. Cholesterol proved to be a key molecule for the function of synapses as its depletion resulted in a significant reduction of both NMDA receptor (NMDAR) and AMPA/kainate receptor-mediated evoked excitatory postsynaptic currents (eEPSCs), by 94% and 72%, respectively. We identified two presynaptic and two postsynaptic steps of synaptic transmission which are modulated by cholesterol and explain together the above-mentioned reduction of eEPSCs. In the postsynapse, we show that physiological levels of cholesterol are important for maintaining the normal probability of opening of NMDARs and for keeping NMDARs localized in synapses. In the presynapse, our results favour the hypothesis of a role of cholesterol in the propagation of axonal action potentials. Finally, cholesterol is a negative modulator of spontaneous presynaptic glutamate release. Our study identifies cholesterol as an important endogenous regulator of synaptic transmission and provides insight into molecular mechanisms underlying the neurological manifestation of diseases associated with impaired cholesterol synthesis or decomposition.
Highlights
Cholesterol is a structural component of cellular membranes enriched in synapses but its role in synaptic transmission remains poorly understood
We found that acute cholesterol depletion from neuronal membranes by methyl-β-cyclodextrin (MβCD) induced a substantial decrease of the probability of opening of NMDA receptors (NMDAR) while AMPA/kainate receptor (AMPAR) function was unaffected[3]
NMDAR and AMPAR evoked excitatory postsynaptic currents (eEPSCs) were recorded in hippocampal autaptic neurons under control conditions and after 5 min of 5, 10 or 20 mM MβCD pretreatment (Fig. 1A–I)
Summary
Cholesterol is a structural component of cellular membranes enriched in synapses but its role in synaptic transmission remains poorly understood. We found that acute cholesterol depletion from neuronal membranes by methyl-β-cyclodextrin (MβCD) induced a substantial decrease of the probability of opening of NMDA receptors (NMDAR) while AMPA/kainate receptor (AMPAR) function was unaffected[3]. This showed that naturally occurring cholesterol controls the function of NMDARs. Plasma membrane cholesterol distribution is not uniform and both presynaptic and postsynaptic membranes are reported to be enriched in cholesterol[5,6] which suggests an important role of cholesterol in synaptic transmission. Niemann-Pick type C disease and Smith-Lemli-Opitz syndrome, both presenting
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