LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery.
Neurotransmitter receptor trafficking during synaptic plasticity requires the concerted action of multiple signaling pathways and the protein transport machinery. However, little is known about the contribution of lipid metabolism during these processes. In this paper, we addressed the question of the role of cholesterol in synaptic changes during long-term potentiation (LTP). 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. 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.
Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Anna
A
Brachet
Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Stephanie
S
Norwood
Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3508 Utrecht, Netherlands.
Jos F
JF
Brouwers
Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Ernest
E
Palomer
Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3508 Utrecht, Netherlands.
J Bernd
JB
Helms
Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain cdotti@cbm.csic.es jaesteban@cbm.csic.es.
Carlos G
CG
Dotti
Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain cdotti@cbm.csic.es jaesteban@cbm.csic.es.
José A
JA
Esteban
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D017774:Long-Term Potentiation; D009473:Neuronal Plasticity; D009474:Neurons / Q000502:physiology; D021381:Protein Transport; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D009435:Synaptic Transmission; D046509:Tissue Culture Techniques; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
D002784:Cholesterol; D018091:Receptors, AMPA; D020764:cdc42 GTP-Binding Protein; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins