AMPAR trafficking in synapse maturation and plasticity

Abstract

Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate most fast excitatory synaptic transmission in the central nervous system. The content and composition of AMPARs in postsynaptic membranes (which determine synaptic strength) are dependent on the regulated trafficking of AMPAR subunits in and out of the membranes. AMPAR trafficking is a key mechanism that drives nascent synapse development, and is the main determinant of both Hebbian and homeostatic plasticity in mature synapses. Hebbian plasticity seems to be the biological substrate of at least some forms of learning and memory; while homeostatic plasticity (also known as synaptic scaling) keeps neuronal circuits stable by maintaining changes within a physiological range. In this review, we examine recent findings that provide further understanding of the role of AMPAR trafficking in synapse maturation, Hebbian plasticity, and homeostatic plasticity.

Fig. 1

a Schematic illustration of AMPAR tetramer in the membrane. Tetrameric AMPARs are assembled from two dimers of distinct subunits. b Schematic illustration of structure of GluA subunit. All GluA subunits consist of three transmembrane domains (M1, M2, and M3), one re-entrant loop (P), an extracellular N-terminal domain (ATD or NTD) and a C-terminal intracellular region. Each GluA subunit is composed of a large extracellular ligand-binding core (segments S1 and S2) that serves as binding site for glutamate. The Q/R editing site controls Ca²⁺ flux and receptor tetramerization, whereas alternative splice flip and flop variants control gating kinetics

Fig. 2

Schematic illustrating AMPAR and NMDAR structure, with interacting molecules, at nascent and maturing glutamatergic synapses. a Nascent synapse. During synaptogenesis, spontaneous activity induces GluA4-containing AMPARs incorporation into synapses that mediate fast excitatory transmission. Interaction between the NTD of the GluA4 subunit and neuronal pentraxin (NP1) (secreted by the presynaptic neurons) controls synaptic recruitment of GluA4. However, AMPAR signaling is not stable and the receptor easily switches between labile and silent states. A developmental switch from GluN2B to GluN2A subunits in NMDARs, mediated by the PSD95 scaffold protein, results in increased AMPAR currents and leads to a mature synapse. b Mature synapse: here number, synaptic localization and subunit composition of AMPARs are regulated by various transmembrane and cytosol proteins

Fig. 3

Schematic illustration of known molecular players and mechanisms involved in long-term depression (left) and long-term potentiation (right). Long-term depression (LTD) is characterized by endocytosis of GluA2-containing AMPARs from synapses and consequent weakening of synaptic strength. LTD is induced by sustained low-level postsynaptic calcium influx as a result of low-frequency glutamate stimulation. The slow rise in intracellular calcium selectively activates phosphatases and kinases of intracellular signaling pathways that effect changes contributing to LTD. Thus, PKC is activated to phosphorylate Ser880 on GluA2, which in turn decreases GluA2 affinity for GRIP-anchoring proteins, and increases GluA2 affinity for PICK1. PICK1-binding enhances AMPAR endocytosis, which occurs in clathrin-positive zones adjacent to the post synaptic density (PSD). By contrast, Tyr876 dephosphorylation allows GluA2 binding to BRAG2 leading to the Arf6 activation crucial for AMPAR internalization. Long-term potentiation is characterized by a marked increase in AMPARs at the synapse with consequent increase in synaptic strength. LTP is induced by high presynaptic glutamate levels which activate postsynaptic NMDARs, leading to a strong calcium influx, followed by further calcium influx though CP-AMPARs. The strong calcium influx activates kinases (PKC, PKA, and CAMKII) involved in GluA1 phosphorylation. GluA1 phosphorylation induces AMPAR exocytosis in extrasynaptic regions. Another consequence of the initiation of LTP is that recycling endosomes deliver AMPARs to the membrane at domains enriched in Stx4, which mediates fusion of endosome with the membrane. Finally, AMPARs diffuse laterally to the synapse and are anchored there by scaffold proteins