Abstract
Experience-dependent learning and memory require multiple forms of plasticity at hippocampal and cortical synapses that are regulated by N-methyl-D-aspartate receptors (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors (NMDAR, AMPAR). These plasticity mechanisms include long-term potentiation (LTP) and depression (LTD), which are Hebbian input-specific mechanisms that rapidly increase or decrease AMPAR synaptic strength at specific inputs, and homeostatic plasticity that globally scales-up or -down AMPAR synaptic strength across many or even all inputs. Frequently, these changes in synaptic strength are also accompanied by a change in the subunit composition of AMPARs at the synapse due to the trafficking to and from the synapse of receptors lacking GluA2 subunits. These GluA2-lacking receptors are most often GluA1 homomeric receptors that exhibit higher single-channel conductance and are Ca2+-permeable (CP-AMPAR). This review article will focus on the role of protein phosphorylation in regulation of GluA1 CP-AMPAR recruitment and removal from hippocampal synapses during synaptic plasticity with an emphasis on the crucial role of local signaling by the cAMP-dependent protein kinase (PKA) and the Ca2+calmodulin-dependent protein phosphatase 2B/calcineurin (CaN) that is coordinated by the postsynaptic scaffold protein A-kinase anchoring protein 79/150 (AKAP79/150).
Highlights
Long-term potentiation (LTP) and depression (LTD) can be induced by brief, strong vs. prolonged, weak activation of N-methyl-D-aspartate receptor (NMDAR) Ca2+ influx and are expressed by long-lasting increases or decreases, respectively, in α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid receptor (AMPAR) activity
By avoiding complications associated with mutating the AMPARs themselves and instead focusing on manipulating upstream kinase/phosphatase regulatory mechanisms, the knock-in mouse studies described above characterizing the roles of AKAP-anchored protein kinase (PKA), CaN, and S-palmitoylation in long-term potentiation (LTP)/LTD have provided a substantial amount of additional evidence for the importance of GluA1 Serine 845 (S845) phosphorylation and CP-AMPARs in regulating hippocampal synaptic plasticity
A number of important questions remain to be addressed with respect to the CP-AMPAR regulation of synaptic plasticity
Summary
Long-term potentiation (LTP) and depression (LTD) can be induced by brief, strong vs. prolonged, weak activation of N-methyl-D-aspartate receptor (NMDAR) Ca2+ influx and are expressed by long-lasting increases or decreases, respectively, in α-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid receptor (AMPAR) activity. While GluA2-lacking, GluA1 homomeric CP-AMPARs are largely excluded from hippocampal synapses basally (Lu et al, 2009; Rozov et al, 2012), both Hebbian and homeostatic plasticity can modify synaptic strength via recruiting CP-AMPARs to synapses (Thiagarajan et al, 2005; Plant et al, 2006; Sutton et al, 2006; Lu et al, 2007; Aoto et al, 2008; Yang et al, 2010; Soares et al, 2013; Park et al, 2016; Sanderson et al, 2016; but see Adesnik and Nicoll, 2007; Ancona Esselmann et al, 2017) These recruited CP-AMPARs, due to both greater single-channel conductance and Ca2+ permeability described above, can in turn influence the level of plasticity expression and confer changes in synaptic signaling resulting in the plasticity of plasticity i.e., metaplasticity. While there is strong evidence to Frontiers in Synaptic Neuroscience | www.frontiersin.org
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