Phosphorylation of AMPA Receptors Is Required for Sensory Deprivation-Induced Homeostatic Synaptic Plasticity

Abstract

Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca2+-permeable AMPA receptors (CP-AMPARs). However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1) subunit at the serine 845 (S845) site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants), which is a substrate of cAMP-dependent kinase (PKA), show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity.

Extensive phosphorylation of AMPA receptors in neurons

“…3 G and H). These results show that phospho-GluA1-containing receptors make up a significant fraction of the total receptor population, and that this phospho-population is regulated under plasticity conditions, in agreement with earlier work (9,17,(31)(32)(33)(34).…”

“…Rat cortical neurons were treated with NMDA or glycine, chemical stimuli shown to induce LTD or LTP, respectively (cLTD/cLTP), and which are known to regulate S845 phosphorylation (26)(27)(28). Alternatively, neurons were treated with Iso, a noradrenaline analog known to result in phosphorylation of GluA1 S845 via activation of β-adrenergic receptors and PKA (10,17,23,29,30). cLTD treatment significantly reduced the levels of phospho-S845, whereas cLTP and Iso increased the signal of phospho-S845 (Fig.…”

“…Perhaps the strongest evidence for roles of GluA1 S845 and S831 phosphorylation comes from studies of mice with knockin mutations in which GluA1 phosphorylation is disrupted or mimicked. Several forms of behavior and synaptic plasticity in multiple brain regions require S845 or S831 phosphorylation, including hippocampal/cortical LTP and LTD, homeostatic plasticity, modulation of plasticity by neuromodulators, hippocampal spatial memory, fear-learning/extinction, appetitive incentive learning, and the action of antidepressants (8,(10)(11)(12)(17)(18)(19)(20)(21)(22)(23).…”

Synaptic AMPA receptor composition in development, plasticity and disease

“… Visual depravation through dark-rearing rats increases AMPAR EPSCs at layer 2/3 pyramidal neurons in visual cortex but reduces them in somatosensory and auditory cortices 154 . The in vivo homeostatic upscaling in the visual cortex is mediated via increased CP-AMPARs and is absent in GluA1-S845A mice 155 .  In fear conditioning a conditioned stimulus (e.g.…”

Experience-dependent homeostasis of ‘noise’ at inhibitory synapses preserves information coding in adult visual cortex

“…In addition to the alterations in mIPSC frequency that we describe here, visual deprivation also increases the strength of excitatory synapses [17,22,23,42,43]. In theory, the increase in the strength of individual excitatory synapses combined with reduction in input activity, due to visual deprivation, on their own could allow preservation of mean input current.…”