Brachet Anna, Norwood Stephanie, Brouwers Jos F, Palomer Ernest, Helms J Bernd, Dotti Carlos G, Esteban José A
Departamento de Neurobiología, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, 3508 Utrecht, Netherlands.
J Cell Biol. 2015 Mar 16;208(6):791-806. doi: 10.1083/jcb.201407122. Epub 2015 Mar 9.
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.
突触可塑性过程中的神经递质受体运输需要多种信号通路和蛋白质运输机制的协同作用。然而，对于脂质代谢在这些过程中的作用却知之甚少。在本文中，我们探讨了胆固醇在长时程增强（LTP）期间突触变化中的作用问题。我们发现，LTP诱导过程中N-甲基-D-天冬氨酸型谷氨酸受体（NMDAR）的激活导致神经元内胆固醇的快速且持续丢失或重新分布。反过来，胆固醇的减少会导致Cdc42的激活以及含GluA1的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体（AMPAR）从Rab11循环内体转运到突触膜，从而导致突触增强。这一过程伴随着NMDAR功能的增加和LTP的增强。这些结果表明，胆固醇作为NMDAR激活的传感器，并作为下游信号的触发因素，在LTP期间参与小GTP酶（鸟苷三磷酸酶）的激活和AMPAR的突触传递。
