Contribution of cytoskeleton to the internalization of AMPA receptors.

Trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) at synapses has been suggested to play an important role in the expression of synaptic plasticity. Both the regulated and the constitutive trafficking of synaptic AMPARs are thought to involve the insertion and removal of receptors by means of an exocytotic and endocytotic process, respectively. In contrast, N-methyl-d-aspartate (NMDA) receptors (NMDARs), which are colocalized with AMPARs at excitatory synapses, appear to be much less dynamic. Here, we present evidence supporting the idea that synaptic AMPARs turn over through a constitutive endocytotic process and that glutamate application greatly enhances this turnover of AMPARs. The glutamate-induced internalization of AMPARs requires a rise in postsynaptic Ca(2+). The AMPAR internalization is mimicked by latrunculin A, a drug that selectively depolymerizes actin and is blocked by jasplakinolide, a drug which stabilizes actin filaments. The rate of endocytosis is not altered by glutamate application, whereas a clear enhancement is observed with insulin application. We propose a model in which the glutamate-induced dissociation of AMPARs from their anchor on the postsynaptic membrane involves actin depolymerization, which allows the released AMPARs to segregate from the NMDARs and diffuse to a presumably perisynaptic site, where they become available to an endocytotic machinery and are selectively internalized.