Cholesterol is an important constituent of cell membranes and plays a crucial role in the compartmentalization of the plasma membrane and signaling. Brain cholesterol accounts for a large proportion of the body’s total cholesterol, existing in two pools: the plasma membranes of neurons and glial cells and the myelin membranes . Cholesterol has been recently shown to be important for synaptic transmission, and a link between cholesterol metabolism defects and neurodegenerative disorders is now recognized. Many neurodegenerative diseases are characterized by impaired cholesterol turnover in the brain. However, at which stage the cholesterol biosynthetic pathway is perturbed and how this contributes to pathogenesis remains unknown. Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction. Defects in cholesterol biosynthesis can trigger dysfunction of synaptic transmission. In this review, an overview of cholesterol turnover under physiological and pathological conditions is presented (Huntington’s, Niemann-Pick type C diseases, Smith-Lemli-Opitz syndrome). We will discuss possible mechanisms by which cholesterol content in the plasma membrane influences synaptic processes. Changes in cholesterol metabolism in Alzheimer’s disease, Parkinson’s disease, and autistic disorders are beyond the scope of this review and will be summarized in our next paper.

In our previous review, we described brain cholesterol metabolism in control conditions and in the case of some rare neurological pathologies linked to defects in the genes which are directly involved in the synthesis and/or traffic of cholesterol. Here, we have analyzed disruptions in cholesterol homeostasis in widespread neurodegenerative diseases (Alzheimer’s and Parkinson’s diseases) and autism spectrum disorders. We particularly focused on the synaptic dysfunctions that could arise from changes in both membrane cholesterol availability and oxysterol production. Notably, alterations in the brain cholesterol metabolism and neurotransmission occur in the early stages of these pathologies and the polymorphism of the genes associated with cholesterol homeostasis and synaptic communication affects the risk of onset and severity of these diseases. In addition, pharmacological and genetic manipulations of brain cholesterol homeostasis in animal models frequently have marked effects on the progression of neurodegenerative diseases. Thus, the development of Alzheimer’s, Parkinson’s and autism spectrum disorders may be partially associated with an imbalance of cholesterol homeostasis that leads to changes in the membrane cholesterol and oxysterol levels that, in turn, modulates key steps in the synaptic transmission.

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Experiments on frog neuromuscular preparations using electrophysiological (two-electrode voltage clamping) and optical (with the fluorescent endocytic stain FM1-43) methods were performed to study the importance of membrane cholesterol in the exo- and endocytic cycle of synaptic vesicles (SV) in motor nerve endings in conditions of prolonged rhythmic stimulation of the motor nerve (20 impulses/sec, 3 min). Extraction of cholesterol from the superficial plasma membranes using methyl-beta-cyclodextrin (1 mM) led to marked changes in SV recycling. There was weakening of SV exocytosis and suppression of processes leading to the recovery of SV populations with rapid readiness to release neurotransmitter. When cholesterol was leached from the outer membranes and the membranes of SV undergoing recycling, these effects were supplemented by impairments to SV endocytosis and recycling. Thus, plasma membrane cholesterol plays a key role in the processes of exocytosis, while the efficiency of endocytosis depends on cholesterol in SV membranes.

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