Abstract
Changes in glutamatergic synaptic strength in brain are dependent on AMPA-type glutamate receptor (AMPAR) recycling, which is assumed to occur through a single local pathway. In this study, we present evidence that AMPAR recycling occurs through different pathways regulated by synaptic activity. Without synaptic stimulation, most AMPARs recycled in dynamin-independent endosomes containing the GTPase, Arf6. Few AMPARs recycled in dynamin-dependent endosomes labeled by transferrin receptors (TfRs). AMPAR recycling was blocked by alterations in the GTPase, TC10, which co-localized with Arf6 endosomes. TC10 mutants that reduced AMPAR recycling had no effect on increased AMPAR levels with long-term potentiation (LTP) and little effect on decreased AMPAR levels with long-term depression. However, internalized AMPAR levels in TfR-containing recycling endosomes increased after LTP, indicating increased AMPAR recycling through the dynamin-dependent pathway with synaptic plasticity. LTP-induced AMPAR endocytosis is inconsistent with local recycling as a source of increased surface receptors, suggesting AMPARs are trafficked from other sites.
Highlights
NMDA- and AMPA-type glutamate receptors (NMDARs/AMPARs) are the major excitatory synaptic receptors in brain
The findings of this study are consistent with constitutive AMPAR recycling occurring largely through a pathway different from the clathrin-dependent pathway used by transferrin receptors (TfRs)
The data in support of an alternative recycling pathway are that internalized AMPARs co-localize much more with Arf6 than with TfRs (Figure 2), and that inhibition of dynamin function blocks TfR endocytosis without significantly altering AMPAR endocytosis (Figure 3)
Summary
NMDA- and AMPA-type glutamate receptors (NMDARs/AMPARs) are the major excitatory synaptic receptors in brain. They are held at post-synaptic densities (PSDs) by scaffold proteins aligning the receptors with the presynaptic glutamate release sites. During LTP, REs move from the dendritic shaft into synaptic spines (Park et al, 2006) from which regulated exocytosis of AMPARs appears to occur. It is uncertain whether AMPARs are exocytosed outside of the spines and traffic to
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