Cholesterol is essential for neuronal activity and function. Cholesterol depletion in the plasma membrane impairs synaptic transmission. Age-related cholesterol reduction is linked to reduced synaptic activity, and defects in synaptic transmission by cholesterol deficiency could result in neurodegeneration. However, the molecular mechanisms by which cholesterol deficiency leads to defects in vesicle fusion remain poorly understood.
Here we show that cholesterol is required for Ca2+-dependent fusion by strengthening membrane bending. We have used the interdisciplinary approaches from biophysics, cellular neurobiology, and electrophysiology: the in-vitro reconstitution of vesicle fusion, human iPSC-derived cortical neurons, and amperometry to monitor exocytosis in chromaffin cells.
Cholesterol strengthens local membrane bending induced by synaptotagmin-1 insertion, thereby lowering the energy barrier for Ca2+-dependent fusion to occur. Our data provide evidence that cholesterol depletion abolishes Ca2+-dependent vesicle fusion by disrupting synaptotagmin-1-induced membrane bending, and suggests that cholesterol is an essential lipid regulator for Ca2+-dependent fusion.
Our data explain the molecular mechanisms of how cholesterol contributes to synaptic transmission and neuronal function and may pave the way for the development of studies to explore the treatment of neurodegenerative and neurodevelopmental disorders.