Long Term Synaptic Depression That Is Associated with GluR1 Dephosphorylation but Not α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Internalization

Davies, Kurtis D.; Goebel-Goody, Susan; Coultrap, Steven J.; Browning, Michael

doi:10.1074/jbc.m803431200

Cited by 22 publications

(27 citation statements)

References 52 publications

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“…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).…”

Section: Quantification Of Phospho-glua1 Containing Ampar Tetramers Usupporting

confidence: 79%

Extensive phosphorylation of AMPA receptors in neurons

Diering

Heo

Hussain

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of AMPA receptor (AMPAR) function is a fundamental mechanism controlling synaptic strength during long-term potentiation/depression and homeostatic scaling. AMPAR function and membrane trafficking is controlled by protein-protein interactions, as well as by posttranslational modifications. Phosphorylation of the GluA1 AMPAR subunit at S845 and S831 play especially important roles during synaptic plasticity. Recent controversy has emerged regarding the extent to which GluA1 phosphorylation may contribute to synaptic plasticity. Here we used a variety of methods to measure the population of phosphorylated GluA1-containing AMPARs in cultured primary neurons and mouse forebrain. Phosphorylated GluA1 represents large fractions from 12% to 50% of the total population under basal and stimulated conditions in vitro and in vivo. Furthermore, a large fraction of synapses are positive for phospho-GluA1-containing AMPARs. Our results support the large body of research indicating a prominent role of GluA1 phosphorylation in synaptic plasticity. up from the subunits GluA1-4, mediate the majority of the fast excitatory synaptic transmission in the central nervous system (1). Regulation of AMPAR function is highly dynamic and represents a fundamental mechanism to control synaptic strength for many forms of synaptic plasticity, including long-term potentiation and depression (LTP/LTD) and homeostatic scaling (1).The function and membrane trafficking of AMPARs is regulated by multiple interacting proteins, as well as by posttranslational modifications, including phosphorylation, palmitoylation, and ubiquitination (1). In particular, phosphorylation of GluA1 at S845 by cyclic-AMP-dependent protein kinase (PKA) (2) and at S831 by calcium/calmodulin-dependent protein kinase II (CaMKII) or protein kinase C (PKC) (3, 4) have been extensively studied. PKA-mediated phosphorylation of GluA1 S845 has been shown to promote GluA1 cell-surface insertion and synaptic retention, increase channel open-probability, facilitate the induction of LTP, and mediate homeostatic scaling-up, whereas dephosphorylation of S845 is associated with receptor endocytosis, LTD, and homeostatic scaling-down (5-13). CaMKII-mediated phosphorylation of GluA1 S831 increases channel conductance and regulates LTP (8,(13)(14)(15)(16). 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).A recent study (24) used a variant of SDS/PAGE, called Phostag, to quantify the stoichiometry of GluA1 S845/S831 phosphorylation. Surprisingly, the authors of th...

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Section: Quantification Of Phospho-glua1 Containing Ampar Tetramers Usupporting

confidence: 79%

Extensive phosphorylation of AMPA receptors in neurons

Diering

Heo

Hussain

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Plasticity at excitatory synapses involves alterations in AMPAR subunit composition and trafficking at synaptic membranes (Davies et al, 2008). Accordingly, a reduction in the amplitude of evoked EPSCs and sEPSCs is consistent with either 1) an increase in GluR2 containing channels (MPTP animals) or 2) an increase in GluR2880 expression (MPTP and saline animals) with increase in AMPAR trafficking as seen in exercised animals, or both.…”

Section: Discussionmentioning

confidence: 89%

Altered AMPA receptor expression with treadmill exercise in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐lesioned mouse model of basal ganglia injury

VanLeeuwen

Petzinger

Walsh

et al. 2009

J of Neuroscience Research

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Dopamine depletion leads to impaired motor performance and increased glutamatergic-mediated hyperexcitability of medium spiny neurons in the basal ganglia. Intensive treadmill exercise improves motor performance in both saline treatment and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. In the present study, we investigated the effect of high-intensity treadmill exercise on changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit expression, because these receptor channels confer the majority of fast excitatory neurotransmission in the brain, and their subunit composition provides a key mechanism for regulating synaptic strength and synaptic neuroplasticity and is important in modulating glutamatergic neurotransmission. Within the dorsolateral striatum of MPTP mice, treadmill exercise increased GluR2 subunit expression, with no significant effect on GluR1. Furthermore, neurophysiological studies demonstrated a reduction in the size of excitatory postsynaptic currents (EPSCs) in striatal medium spiny neurons (as determined by the input-output relationship), reduced amplitude of spontaneous EPSCs, and a loss of polyamine-sensitive inward rectification, all supportive of an increase in heteromeric AMPAR channels containing the GluR2 subunit. Phosphorylation of GluR2 at serine 880 in both saline-treated and MPTP mice suggests that exercise may also influence AMPAR trafficking and thus synaptic strength within the striatum. Finally, treadmill exercise also altered flip isoforms of GluR2 and GluR1 mRNA transcripts. These findings suggest a role for AMPARs in mediating the beneficial effects of exercise and support the idea that adaptive changes in GluR2 subunit expression may be important in modulating experience-dependent neuroplasticity of the injured basal ganglia.

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“…These procedures were developed based on the insolubility of the postsynaptic density and synaptic junctions in Triton X-100 as described previously (Davies et al, 2007; 2008; Goebel-Goody et al, 2009; Ferrario et al, 2011b). Briefly, rats were decapitated immediately after rats were anesthetized with equithesin (5 ml/kg, i.p.).…”

Section: Methodsmentioning

confidence: 99%

Rapid and sustained GluA1 S845 phosphorylation in synaptic and extrasynaptic locations in the rat forebrain following amphetamine administration

Xue

Edwards

Mao

et al. 2014

Neurochemistry International

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The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is a major ionotropic glutamate receptor subtype in the mammalian brain. Like other glutamate receptors, the AMPA receptor is regulated by phosphorylation. By phosphorylating specific serine resides in AMPA receptor subunits (GluA1 and GluA2), various protein kinases regulate subcellular/subsynaptic expression and function of the receptor. In this study, we conducted a time course study to evaluate the temporal property of responses of phosphorylation at those sites to dopamine stimulation with the psychostimulant amphetamine in the adult rat striatum and medial prefrontal cortex (mPFC) in vivo. We focused on biochemically-enriched AMPA receptors from synaptic and extrasynaptic compartments. We found that acute injection of amphetamine induced a rapid and relatively sustained increase in GluA1 S845 phosphorylation at both synaptic and extrasynaptic sites in the striatum. Similar results were observed in the mPFC. In contrast to S845, amphetamine did not induce a significant change in GluA1 S831 phosphorylation in synaptic and extrasynaptic pools in the striatum and mPFC. GluA2 S880 phosphorylation in synaptic and extrasynaptic fractions in the two brain regions also remained stable in response to amphetamine. These results support S845 to be a principal site on AMPA receptors sensitive to acute stimulant exposure. Its phosphorylation levels are rapidly upregulated by amphetamine in the two defined subsynaptic microdomains (synaptic versus extrasynaptic locations) in striatal and cortical neurons.

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Long Term Synaptic Depression That Is Associated with GluR1 Dephosphorylation but Not α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Internalization

Cited by 22 publications

References 52 publications

Extensive phosphorylation of AMPA receptors in neurons

Extensive phosphorylation of AMPA receptors in neurons

Altered AMPA receptor expression with treadmill exercise in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐lesioned mouse model of basal ganglia injury

Rapid and sustained GluA1 S845 phosphorylation in synaptic and extrasynaptic locations in the rat forebrain following amphetamine administration

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