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Cholesterol modulates presynaptic and postsynaptic properties of excitatory synaptic transmission

Korinek, Miloslav, Gonzalez-Gonzalez, Inmaculada M., Smejkalova, Tereza, Hajdukovic, Dragana, Skrenkova, Kristyna, Krusek, Jan, Horak, Martin, Vyklicky, Ladislav·2020·Scientific Reports
DOI 10.1038/s41598-020-69454-5PMC PMC7387334
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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.

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Authors
Korinek, M., Gonzalez-Gonzalez, I. M., Smejkalova, T., Hajdukovic, D., Skrenkova, K., Krusek, J., Horak, M., & Vyklicky, L.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2020-07-28
Volume
10
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-020-69454-5
PMC
PMC7387334
Cited by
93
References
3
Language
en
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