LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery.
Bottom Line: A reduction in cholesterol, in turn, leads to the activation of Cdc42 and the mobilization of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) from Rab11-recycling endosomes into the synaptic membrane, leading to synaptic potentiation.This process is accompanied by an increase of NMDAR function and an enhancement of LTP.These results imply that cholesterol acts as a sensor of NMDAR activation and as a trigger of downstream signaling to engage small GTPase (guanosine triphosphatase) activation and AMPAR synaptic delivery during LTP.
Affiliation: Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain.Show MeSH
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Mentions: After observing that LTP induction leads to a rapid decrease in cholesterol content in CA1 neurons, we decided to test whether an acute cholesterol loss may in turn affect synaptic function. To this end, we used pharmacological approaches, rather than slower genetic interventions or inhibitors of enzymatic activities, to bypass compensatory effects and/or accumulation of intermediary products (Kotti et al., 2006). Endogenous cholesterol was reduced by short time applications (30 min) of MBCD (10 mM) or cholesterol oxidase (Chol Ox) enzyme (10 U/ml). These two manipulations offer complementary information to control for potential nonspecific effects because MBCD is only partially specific for cholesterol (Ohtani et al., 1989) but does not generate additional metabolites, whereas Chol Ox is very specific for cholesterol but generates H2O2 and a ketone derivative of cholesterol as byproducts. As shown in Fig. 2 A, both protocols produced a moderate but significant decrease of cholesterol levels in hippocampal slices, as probed by a fluorescence enzymatic assay. This decrease was stable 1 h after the end of the treatment (Fig. S2 A). Of note, these manipulations initially target plasma membrane cholesterol, but they produced a similar reduction of cholesterol from intracellular membranes (Fig. 2 B), probably because of the extensive exchange between these two pools of cholesterol (Zidovetzki and Levitan, 2007). Importantly, this pharmacological reduction in cholesterol from intracellular membranes was quantitatively similar to the one observed upon cLTP induction (compare Fig. 1 A and Fig. 2 B).
Affiliation: Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain.