The role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity

Abstract

In the mammalian central nervous system, excitatory glutamatergic synapses harness neurotransmission that is mediated by ion flow through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs, which are enriched in the postsynaptic membrane on dendritic spines, are highly dynamic, and shuttle in and out of synapses in an activity-dependent manner. Changes in their number, subunit composition, phosphorylation state, and accessory proteins can all regulate AMPARs and thus modify synaptic strength and support cellular forms of learning. Furthermore, dysregulation of AMPAR plasticity has been implicated in various pathological states and has important consequences for mental health. Here we focus on the mechanisms that control AMPAR plasticity, drawing particularly from the extensive studies on hippocampal synapses, and highlight recent advances in the field along with considerations for future directions.

Keywords: AMPAR; Hebbian plasticity; homeostatic plasticity; synaptic plasticity; synaptic transmission; trafficking.

Figure 1

AMPAR subcellular localization and sites of trafficking. AMPARs are exocytosed at multiple locations in neurons such as the soma (1), dendrites (2) and directly into the spine (3). AMPARs freely diffuse at the cell surface extrasynaptically (4), and are trapped at synapses by interactions with scaffold proteins at the postsynaptic density (PSD) (5).

Figure 2

Lateral diffusion and synaptic retention of AMPARs depends on neuronal activity. AMPAR retention at synapses is regulated by multiple factors. Top left, increasing neuronal activity reduces the surface diffusion of AMPARs at synapses and increases their trapping. Top right, at individual synapses where the presynaptic release has been chronically blocked, GluA1 retention is reduced. Bottom right, PSD-95 acts to retain AMPARs at synapses. Overexpression of PSD-95 increases synaptic AMPAR accumulation, but not overexpression of stargazin (see main text).

Figure 3

Nanodomain organization of AMPARs and PSD partners. Within the spine, AMPARs (1) and PSD-95 (2) are concentrated into sub-diffraction sized clusters. These may reflect the effective positioning of the postsynaptic receptor population opposite presynaptic sites of vesicle fusion (3).

Figure 4

Comparing Hebbian and homeostatic plasticity. During Hebbian forms of plasticity synapses change their number of AMPARs in an input-specific fashion. Different patterns of activity can either cause strengthening (LTP, top left) or weakening of synapses (LTD, bottom left) via AMPAR trafficking. Potentiation or depression is limited to stimulated synapses, and neighbors are unaffected. In contrast, during homeostatic plasticity altered levels of neuronal activity drives changes in synaptic AMPAR number across the entire dendritic arbor. Blocking pre- and postsynaptic spiking with TTX causes AMPARs to accumulate at excitatory synapses (bottom right). Conversely increasing network activity (for example with a GABA_AR antagonist) causes a reduction in synaptic AMPAR (top right). Crucially this form of plasticity conserves the relative strength difference between synapses.