Synaptic connections in the brain are continuously remodeled in response to neuronal activity. This process, known as synaptic plasticity, is widely thought to underlie learning and memory, and to be altered in several cognitive disorders. An important aspect of synaptic plasticity is the regulated movement of neurotransmitter receptors in and out of the synaptic membrane.
Cholesterol is an essential membrane component, and it plays a major role in membrane compartmentalization and trafficking. Although cholesterol only accounts for 2% of the body’s weight, the brain contains 25% of the body’s total cholesterol. The enrichment in cholesterol suggests a relevant role for this lipid in brain function. In fact, it, it is being increasingly recognized that cholesterol homeostasis have a role in neurological diseases. However, the precise role of lipids in neurotransmitter receptor trafficking is virtually unexplored. Here, we hypothesize that cholesterol plays a direct role in neurotransmitter receptor trafficking and therefore contributes to synaptic plasticity.
To test this hypothesis, we are developing genetic tools to manipulate cholesterol levels in living neurons. We take advantage of the fact that neurons possess a unique strategy to metabolize the cholesterol originally provided by astrocytes, through the expression of the enzyme CYP46A1. To alter cholesterol content in a cell autonomous way, we will manipulate the levels of CYP46A1 exclusively in neurons. To evaluate the physiological consequences, electrophysiological recordings and cell biological studies will be performed in organotypic hippocampal slice cultures. Hence, this proposal involves the use of a multidisciplinary approach.
We believe that this project will contribute to define the influence of cholesterol in synaptic plasticity. In addition to its intrinsic value, the knowledge generated should help to understand the cognitive deficits typical of disorders due cholesterol homeostasis genes.
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