Regulatory mechanisms of AMPA receptors in synaptic plasticity

Learning and memory rely on activity-dependent changes in the strength of central glutamatergic synapses (synaptic plasticity). Synaptic plasticity can be bidirectional and depends on the patterning of incoming synaptic activity. Loss of synaptic plasticity causes an inability to learn.AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs), together with kinetically slower NMDA (N-methyl-D-aspartate) receptors (NMDARs), are important transducers of fast synaptic transmission in glutamatergic synapses and are often the target of cellular signalling pathways responsible for regulating synaptic strength during plasticity.Long-term potentiation (LTP) and long-term depression (LTD) are two important forms of bidirectional synaptic plasticity which, while different in molecular mechanisms, can coexist in the same synapse. Depending on the brain region, the origin of LTP and LTD can be presynaptic or postsynaptic.In the CA1 area of the hippocampus, LTP and LTD are predominantly postsynaptic, require Ca2+ influx through NMDARs and are associated with changes in properties and trafficking of synaptic AMPARs.Hippocampal LTP is complex in nature and represents an interaction of different signalling components, including kinases and phosphatases, scaffolding proteins, AMPARs and receptor-interacting proteins, cytoskeletal proteins and local dendritic protein synthesis. These signalling and structural components are functionally interconnected.AMPARs can be composed of several subunits in different brain regions and during different stages of development. In the mature brain, glutamate receptor 2 (GluR2) subunits have a particularly crucial role in determining many functional properties of AMPARs.Subunit composition of synaptic AMPARs regarding GluR2-lacking or GluR2-containing AMPARs can be dynamically altered by synaptic activity and substantially contribute to synaptic strength during different forms of postsynaptic plasticity.Phosphorylation of AMPARs in their C-termini is crucial for the properties of these receptors and their trafficking to synapses.Translocation of signalling molecules, especially calcium/calmodulin-dependent protein kinase II (CaMKII), to active synapses has an essential role in their activity-dependent strengthening during hippocampal LTP.Small G-proteins are critically involved in trafficking of AMPARs and in structural reorganization of synaptic spines associated with plasticity. CaMKs could have a key role in coupling Ca2+ influxes to the activity of small G-proteins.Local dendritic protein synthesis is controlled by synaptic activity in different forms of synaptic plasticity. For example, the GluR1 subunit of AMPARs can be synthesized in the dendritic shaft and spines, and contributes to changes in properties of synaptic AMPARs during LTP and homeostatic synaptic plasticity.