LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery.
Bottom Line: However, little is known about the contribution of lipid metabolism during these processes.We found that N-methyl-d-aspartate-type glutamate receptor (NMDAR) activation during LTP induction leads to a rapid and sustained loss or redistribution of intracellular cholesterol in the neuron.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: LTP was induced on hippocampal slice cultures using a well-characterized pharmacological approach that mimics biochemical and electrophysiological properties of electrically induced LTP (chemical LTP [cLTP]; Otmakhov et al., 2004; Kopec et al., 2006; Arendt et al., 2014). This pharmacological approach was used to maximize the number of synapses undergoing plasticity. For biochemical quantification of endogenous cholesterol, slices were homogenized just after cLTP induction or after a recovery period of 20 min and compared with control (untreated) slices. Liquid chromatography (LC)/mass spectrometry (MS) analysis was used to separately measure cholesterol levels in the plasma membrane and microsomal fractions (enriched in intracellular membranes; see Materials and methods). As shown in Fig. 1 A (left-most graph), no significant change was observed in the plasma membrane fraction. In contrast, a rapid and sustained decrease in cholesterol content was observed in intracellular membranes (Fig. 1 A, microsomal fraction, left graph). This decrease required NMDAR activation, as it was blocked when cLTP was induced in the presence of the NMDAR antagonist AP5 (2-amino-5-phosphonopentanoate; Fig. 1 A, +AP5 graphs).
Affiliation: Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain.