Regulation of AMPA receptor trafficking by secreted protein factors

Abstract

AMPA receptors (AMPARs) mediate the majority of fast excitatory transmission in the brain. Regulation of AMPAR levels at synapses controls synaptic strength and underlies information storage and processing. Many proteins interact with the intracellular domain of AMPARs to regulate their trafficking and synaptic clustering. However, a growing number of extracellular factors important for glutamatergic synapse development, maturation and function have emerged that can also regulate synaptic AMPAR levels. This mini-review highlights extracellular protein factors that regulate AMPAR trafficking to control synapse development and plasticity. Some of these factors regulate AMPAR clustering and mobility by interacting with the extracellular N-terminal domain of AMPARs whereas others regulate AMPAR trafficking indirectly via their respective signaling receptors. While several of these factors are secreted from neurons, others are released from non-neuronal cells such as glia and muscle. Although it is apparent that secreted factors can act locally on neurons near their sites of release to coordinate individual synapses, it is less clear if they can diffuse over longer ranges to coordinate related synapses within a circuit or region of the brain. Given that there are hundreds of factors that can be secreted from neuronal and non-neuronal cells, it will not be surprising if more extracellular factors that modulate AMPARs and glutamatergic synapses are discovered. Many open questions remain including where and when the factors are expressed, what regulates their secretion from different cell types, what controls their diffusion, stability, and range of action, and how their cognate receptors influence intracellular signaling to control AMPAR trafficking.

Keywords: AMPAR; regulation; secreted factors; synapse; trafficking.

FIGURE 1

Protein factors secreted from neurons, glia or muscle regulate AMPAR trafficking and synaptic levels. Netrin is released in an activity-dependent manner from neurons and results in an autocrine activation of its receptor DCC. Downstream activation of CaMKII leads to increased delivery of GluA1-containing AMPARs to synapses. BDNF is also secreted from neurons in an activity-dependent manner and activates the tyrosine kinase receptor TrkB and downstream Ras and Erk signaling to increase AMPAR transcription, translation and synaptic incorporation. BDNF can also be secreted from glia (not shown). Noelin and NPTX are secreted from neurons, and act as extracellular scaffolds by interacting with the N-terminal domain of AMPARs and a network of proteins including ECM components. Glia such as astrocytes secrete Gpc4/6 which acts on presynaptic RPTPs leading to the release of NPTX. Chrdl1 acts via an unidentified receptor and signaling pathway to promote synapse maturation during development by inducing the switch to calcium-impermeable GluA2-containing AMPARs. TNFα is secreted from glia in an activity-dependent manner and activates the TNFR and downstream PI3 kinase to upregulate synaptic AMPARs during homeostatic synaptic scaling. In Drosophila, Wg is released from specialized glia that regulate glutamate receptor cluster size and synaptic localization via its receptor DFrizzled. In C. elegans, PVF-1/VEGF secreted by muscle promotes surface levels of AMPARs in distal neurons via its receptor VER-1 and VER-4. PVF-1 and the VERs are thought to promote surface levels of AMPARs via long-distance recycling via retromer. In mammals, VEGF also promotes AMPAR levels at synapses and can be secreted from many cells including neurons, glia and muscle, although it is not known if muscle-derived VEGF regulates AMPARs in mammals. Red arrows represent activity-dependent regulation of the secreted factor.