Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization

Redistribution of postsynaptic AMPA- (alpha-amino-3-hydroxy-5-methylisoxazo le-4-propionic acid-) subtype glutamate receptors may regulate synaptic str ength at glutamatergic synapses, but the mediation of the redistribution is poorly understood. We show that AMPA receptors underwent clathrin-dependen t endocytosis, which was accelerated by insulin in a GluR2 subunit-dependen t manner. Insulin-stimulated endocytosis rapidly decreased AMPA receptor nu mbers in the plasma membrane, resulting in long-term depression (LTD) of AM PA receptor-mediated synaptic transmission in hippocampal CA1 neurons. More over, insulin-induced LTD and low-frequency stimulation-(LFS-) induced homo synaptic CA1 LTD were found to be mutually occlusive and were both blocked by inhibiting postsynaptic clathrin-mediated endocytosis. Thus, controlling postsynaptic receptor numbers through endocytosis may be an important mech anism underlying synaptic plasticity in the mammalian CNS.