State-dependent Ras signaling and AMPA receptor trafficking

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Abstract
Synaptic trafficking of AMPA-Rs, controlled by small GTPase Ras signaling, plays a key role in synaptic plasticity. However, how Ras signals synaptic AMPA-R trafficking is unknown. Here we show that low levels of Ras activity stimulate extracellular signal-regulated kinase kinase (MEK)–p42/44 MAPK (extracellular signal-regulated kinase [ERK]) signaling, whereas high levels of Ras activity stimulate additional Pi3 kinase (Pi3K)–protein kinase B (PKB) signaling, each accounting for ∼50% of the potentiation during long-term potentiation (LTP). Spontaneous neural activity stimulates the Ras–MEK–ERK pathway that drives GluR2L into synapses. In the presence of neuromodulator agonists, neural activity also stimulates the Ras–Pi3K–PKB pathway that drives GluR1 into synapses. Neuromodulator release increases with increases of vigilance. Correspondingly, Ras–MEK–ERK activity in sleeping animals is sufficient to deliver GluR2L into synapses, while additional increased Ras–Pi3K–PKB activity in awake animals delivers GluR1 into synapses. Thus, state-dependent Ras signaling, which specifies downstream MEK–ERK and Pi3K–PKB pathways, differentially control GluR2L- and GluR1-dependent synaptic plasticity.