Abstract
The tuning of glutamatergic transmission is an essential mechanism for neuronal communication. α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are ionotropic glutamate receptors that mediate fast synaptic transmission. The phosphorylation states of specific serine residues on the GluA1 and GluA2 AMPAR subunits are considered critical post-translational modifications that regulate AMPAR activity and subcellular trafficking. While behavioral stress, via stress hormones, exerts specific alterations on such glutamatergic processes, there have been conflicting data concerning the influence of stress on AMPAR phosphorylation in different brain regions, and the post-stress signaling mechanisms mediating these processes are not well delineated. Here, we examined the dynamics of phosphorylation at three AMPAR serine residues (ser831-GluA1, ser845-GluA1, and ser880-GluA2) in four brain regions [amygdala, medial prefrontal cortex (mPFC), dorsal hippocampus, and ventral hippocampus] of the rat during the hour following behavioral stress. We also tested the impact of post-stress corticosteroid receptor blockade on AMPAR phosphorylation. Both GluA1 subunit residues exhibited elevated phosphorylation after stress, yet post-stress administration of corticosteroid receptor antagonists curtailed these effects only at ser831-GluA1. In contrast, ser880-GluA2 displayed a time-dependent tendency for early decreased phosphorylation (that was selectively augmented by mifepristone treatment in the amygdala and mPFC of stressed animals) followed by increased phosphorylation later on. These findings show that the in vivo regulation of AMPAR phosphorylation after stress is a dynamic and subunit-specific process, and they provide support for the hypothesis that corticosteroid receptors have an ongoing role in the regulation of ser831-GluA1 phosphorylation during the post-stress interval.
Similar content being viewed by others
References
Abraham WC (2008) Metaplasticity: tuning synapses and networks for plasticity. Nat Rev Neurosci 9(5):387
Alzamora R, Harvey BJ (2008) Direct binding and activation of protein kinase C isoforms by steroid hormones. Steroids 73(9):885–888
Birnbaum SG, Yuan P, Wang M, Vijayraghavan S, Bloom A, Davis D, Gobeske K, Sweatt J, Manji H, Arnsten A (2004) Protein kinase C overactivity impairs prefrontal cortical regulation of working memory. Science 306(5697):882–884
Bogdan R, Pizzagalli DA (2006) Acute stress reduces reward responsiveness: implications for depression. Biol Psychiatry 60(10):1147–1154
Brewin CR, Andrews B, Valentine JD (2000) Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. J Consult Clin Psychol 68(5):748–766
Busto R, Globus MYT, Neary JT, Ginsberg MD (1994) Regional alterations of protein kinase C activity following transient cerebral ischemia: effects of intraischemic brain temperature modulation. J Neurochem 63(3):1095–1103
Caffino L, Calabrese F, Giannotti G, Barbon A, Verheij MM, Racagni G, Fumagalli F (2015) Stress rapidly dysregulates the glutamatergic synapse in the prefrontal cortex of cocaine-withdrawn adolescent rats. Addict Biol 20(1):158–169
Cain CK, Maynard GD, Kehne JH (2012) Targeting memory processes with drugs to prevent or cure PTSD. Expert Opin Investig Drugs 21(9):1323–1350
Caudal D, Godsil BP, Mailliet F, Bergerot D, Jay TM (2010) Acute stress induces contrasting changes in AMPA receptor subunit phosphorylation within the prefrontal cortex, amygdala and hippocampus. PLoS One 5(12):e15282
Caudal D, Jay TM, Godsil BP (2014) Behavioral stress induces regionally-distinct shifts of brain mineralocorticoid and glucocorticoid receptor levels. Frontiers in Behavioral Neuroscience 8:19
Chandran A, Iyo AH, Jernigan CS, Legutko B, Austin MC, Karolewicz B (2013) Reduced phosphorylation of the mTOR signaling pathway components in the amygdala of rats exposed to chronic stress. Prog Neuropsychopharmacol Biol Psychiatry 40:240–245
Chung HJ, Xia J, Scannevin RH, Zhang X, Huganir RL (2000) Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins. J Neurosci 20(19):7258–7267
Chung HJ, Steinberg JP, Huganir RL, Linden DJ (2003) Requirement of AMPA receptor GluR2 phosphorylation for cerebellar long-term depression. Science 300(5626):1751–1755
Cohen H, Matar MA, Buskila D, Kaplan Z, Zohar J (2008) Early post-stressor intervention with high-dose corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress disorder. Biol Psychiatry 64(8):708–717. doi:10.1016/j.biopsych.2008.05.025
Cole M, Kalman B, Pace T, Topczewski F, Lowrey M, Spencer R (2000) Selective blockade of the mineralocorticoid receptor impairs hypothalamic-pituitary-adrenal axis expression of habituation. J Neuroendocrinol 12(10):1034–1042
Conboy L, Sandi C (2010) Stress at learning facilitates memory formation by regulating AMPA receptor trafficking through a glucocorticoid action. Neuropsychopharmacology 35(3):674–685
Corcoran C, Walker E, Huot R, Mittal V, Tessner K, Kestler L, Malaspina D (2003) The stress cascade and schizophrenia: etiology and onset. Schizophr Bull 29(4):671–692
Crombag HS, Sutton JM, Takamiya K, Holland PC, Gallagher M, Huganir RL (2008) A role for alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid GluR1 phosphorylation in the modulatory effects of appetitive reward cues on goal-directed behavior. Eur J Neurosci 27(12):3284–3291
de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6(6):463–475. doi:10.1038/nrn1683
Delgado JY, O’Dell TJ (2005) Long-term potentiation persists in an occult state following mGluR-dependent depotentiation. Neuropharmacology 48(7):936–948
Delgado JY, Coba M, Anderson CN, Thompson KR, Gray EE, Heusner CL, Martin KC, Grant SG, O’Dell TJ (2007) NMDA receptor activation dephosphorylates AMPA receptor glutamate receptor 1 subunits at threonine 840. J Neurosci 27(48):13210–13221
Derkach V, Barria A, Soderling TR (1999) Ca2+/calmodulin-kinase II enhances channel conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc Natl Acad Sci 96(6):3269–3274
Derkach VA, Oh MC, Guire ES, Soderling TR (2007) Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat Rev Neurosci 8(2):101–113
Dorey R, Pierard C, Chauveau F, David V, Beracochea D (2012) Stress-induced memory retrieval impairments: different time-course involvement of corticosterone and glucocorticoid receptors in dorsal and ventral hippocampus. Neuropsychopharmacology 37(13):2870–2880. doi:10.1038/npp.2012.170
Evanson N, Herman J, Sakai R, Krause E (2010) Nongenomic actions of adrenal steroids in the central nervous system. J Neuroendocrinol 22(8):846–861
File SE, Peet LA (1980) The sensitivity of the rat corticosterone response to environmental manipulations and to chronic chlordiazepoxide treatment. Physiol Behav 25(5):753–758
Fink AE, O’Dell TJ (2009) Short trains of theta frequency stimulation enhance CA1 pyramidal neuron excitability in the absence of synaptic potentiation. J Neurosci 29(36):11203–11214. doi:10.1523/JNEUROSCI.1450-09.2009
Fullerton CS, Ursano RJ, Wang L (2004) Acute stress disorder, posttraumatic stress disorder, and depression in disaster or rescue workers. Am J Psychiatry 161(8):1370–1376
Fumagalli F, Pasini M, Frasca A, Drago F, Racagni G, Riva MA (2009) Prenatal stress alters glutamatergic system responsiveness in adult rat prefrontal cortex. J Neurochem 109(6):1733–1744
Fumagalli F, Caffino L, Vogt MA, Frasca A, Racagni G, Sprengel R, Gass P, Riva MA (2011) AMPA GluR-A receptor subunit mediates hippocampal responsiveness in mice exposed to stress. Hippocampus 21(9):1028–1035
Funder JW (1997) Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance. Annu Rev Med 48:231–240. doi:10.1146/annurev.med.48.1.231
Godsil BP, Fanselow MS (2004) Light stimulus change evokes an activity response in the rat. Learn Behav 32(3):299–310
Gray EE, Guglietta R, Khakh BS, O’Dell TJ (2014) Inhibitory Interactions between Phosphorylation Sites in the C Terminus of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid-type Glutamate Receptor GluA1 Subunits. J Biol Chem 289(21):14600–14611
Groc L, Choquet D, Chaouloff F (2008) The stress hormone corticosterone conditions AMPAR surface trafficking and synaptic potentiation. Nat Neurosci 11(8):868–870
Groeneweg FL, Karst H, de Kloet ER, Joels M (2011) Rapid non-genomic effects of corticosteroids and their role in the central stress response. J Endocrinol 209(2):153–167. doi:10.1530/JOE-10-0472
Hammen C, Kim EY, Eberhart NK, Brennan PA (2009) Chronic and acute stress and the prediction of major depression in women. Depress Anxiety 26(8):718–723
Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE (2003) Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol 24(3):151–180. doi:10.1016/j.yfrne.2003.07.001
Holmes A, Wellman CL (2009) Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neurosci Biobehav Rev 33(6):773–783
Hsiao Y-H, Chen PS, Chen S-H, Gean P-W (2011) The involvement of Cdk5 activator p35 in social isolation-triggered onset of early Alzheimer’s disease-related cognitive deficit in the transgenic mice. Neuropsychopharmacology 36(9):1848–1858
Hu H, Real E, Takamiya K, Kang M-G, Ledoux J, Huganir RL, Malinow R (2007) Emotion enhances learning via norepinephrine regulation of AMPA-receptor trafficking. Cell 131(1):160–173
Jarome TJ, Kwapis JL, Werner CT, Parsons RG, Gafford GM, Helmstetter FJ (2012) The timing of multiple retrieval events can alter GluR1 phosphorylation and the requirement for protein synthesis in fear memory reconsolidation. Learn Mem 19(7):300–306
Joels M, Sarabdjitsingh RA, Karst H (2012) Unraveling the time domains of corticosteroid hormone influences on brain activity: rapid, slow, and chronic modes. Pharmacol Rev 64(4):901–938. doi:10.1124/pr.112.005892
Julien C, Marcouiller F, Bretteville A, El Khoury NB, Baillargeon J, Hébert SS, Planel E (2012) Dimethyl sulfoxide induces both direct and indirect tau hyperphosphorylation. PLoS One 7(6):e40020. doi:10.1371/journal.pone.0040020
Karst H, Berger S, Turiault M, Tronche F, Schutz G, Joels M (2005) Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone. Proc Natl Acad Sci USA 102(52):19204–19207. doi:10.1073/pnas.0507572102
Karst H, Berger S, Erdmann G, Schutz G, Joels M (2010) Metaplasticity of amygdalar responses to the stress hormone corticosterone. Proc Natl Acad Sci USA 107(32):14449–14454. doi:10.1073/pnas.0914381107
Kristensen AS, Jenkins MA, Banke TG, Schousboe A, Makino Y, Johnson RC, Huganir R, Traynelis SF (2011) Mechanism of Ca2+/calmodulin-dependent kinase II regulation of AMPA receptor gating. Nat Neurosci 14(6):727–735
Krugers H, Koolhaas J, Bohus B, Korf J (1993) A single social stress-experience alters glutamate receptor-binding in rat hippocampal CA3 area. Neurosci Lett 154(1):73–77
Lee H-K, Barbarosie M, Kameyama K, Bear MF, Huganir RL (2000) Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405(6789):955–959
Lee H-K, Takamiya K, He K, Song L, Huganir RL (2010) Specific roles of AMPA receptor subunit GluR1 (GluA1) phosphorylation sites in regulating synaptic plasticity in the CA1 region of hippocampus. J Neurophysiol 103(1):479–489
Liu Y, Sun QA, Chen Q, Lee TH, Huang Y, Wetsel WC, Michelotti GA, Sullenger BA, Zhang X (2009) Targeting inhibition of GluR1 Ser845 phosphorylation with an RNA aptamer that blocks AMPA receptor trafficking. J Neurochem 108(1):147–157
Liu M, Li J, Dai P, Zhao F, Zheng G, Jing J, Wang J, Luo W, Chen J (2015) Microglia activation regulates GluR1 phosphorylation in chronic unpredictable stress-induced cognitive dysfunction. Stress 18(1):96–106
Mailliet F, Qi H, Rocher C, Spedding M, Svenningsson P, Jay TM (2008) Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors: implication of MEK signaling. Exp Neurol 211(2):593–596. doi:10.1016/j.expneurol.2008.02.030
McEwen BS (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 87(3):873–904. doi:10.1152/physrev.00041.2006
Naik MU, Benedikz E, Hernandez I, Libien J, Hrabe J, Valsamis M, Dow-Edwards D, Osman M, Sacktor TC (2000) Distribution of protein kinase Mζ and the complete protein kinase C isoform family in rat brain. J Comp Neurol 426(2):243–258
Oh MC, Derkach VA, Guire ES, Soderling TR (2006) Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation. J Biol Chem 281(2):752–758
Opazo P, Choquet D (2011) A three-step model for the synaptic recruitment of AMPA receptors. Mol Cell Neurosci 46(1):1–8
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, San Diego
Popoli M, Yan Z, McEwen BS, Sanacora G (2012) The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 13(1):22–37
Qi H, Mailliet F, Spedding M, Rocher C, Zhang X, Delagrange P, McEwen B, Jay TM, Svenningsson P (2009) Antidepressants reverse the attenuation of the neurotrophic MEK/MAPK cascade in frontal cortex by elevated platform stress; reversal of effects on LTP is associated with GluA1 phosphorylation. Neuropharmacology 56(1):37–46. doi:10.1016/j.neuropharm.2008.06.068
Reul JM, de Kloet ER (1985) Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117(6):2505–2511. doi:10.1210/endo-117-6-2505
Richter-Levin G, Maroun M (2010) Stress and amygdala suppression of metaplasticity in the medial prefrontal cortex. Cereb Cortex 20(10):2433–2441. doi:10.1093/cercor/bhp311
Rocher C, Spedding M, Munoz C, Jay TM (2004) Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. Cereb Cortex 14(2):224–229. doi:10.1093/cercor/bhg122
Roozendaal B, McReynolds JR, Van der Zee EA, Lee S, McGaugh JL, McIntyre CK (2009) Glucocorticoid effects on memory consolidation depend on functional interactions between the medial prefrontal cortex and basolateral amygdala. J Neurosci 29(45):14299–14308
Santos S, Carvalho A, Caldeira M, Duarte C (2009) Regulation of AMPA receptors and synaptic plasticity. Neuroscience 158(1):105–125
Seidenman KJ, Steinberg JP, Huganir R, Malinow R (2003) Glutamate receptor subunit 2 Serine 880 phosphorylation modulates synaptic transmission and mediates plasticity in CA1 pyramidal cells. J Neurosci 23(27):9220–9228
Shepherd JD, Huganir RL (2007) The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol 23:613–643
Sorge RE, Martin LJ, Isbester KA, Sotocinal SG, Rosen S, Tuttle AH, Wieskopf JS, Acland EL, Dokova A, Kadoura B (2014) Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat Methods 11(6):629–632
Tsvyetlynska NA, Hill RH, Grillner S (2005) Role of AMPA receptor desensitization and the side effects of a DMSO vehicle on reticulospinal EPSPs and locomotor activity. J Neurophysiol 94(6):3951–3960
Whitehead G, Jo J, Hogg EL, Piers T, Kim D-H, Seaton G, Seok H, Bru-Mercier G, Son GH, Regan P (2013) Acute stress causes rapid synaptic insertion of Ca2+-permeable AMPA receptors to facilitate long-term potentiation in the hippocampus. Brain 136(12):3753–3765
Williams JM, Guévremont D, Mason-Parker SE, Luxmanan C, Tate WP, Abraham WC (2007) Differential trafficking of AMPA and NMDA receptors during long-term potentiation in awake adult animals. J Neurosci 27(51):14171–14178
Yang C-H, Huang C-C, Hsu K-S (2004) Behavioral stress modifies hippocampal synaptic plasticity through corticosterone-induced sustained extracellular signal-regulated kinase/mitogen-activated protein kinase activation. J Neurosci 24(49):11029–11034
Yuen EY, Liu W, Karatsoreos IN, Feng J, McEwen BS, Yan Z (2009) Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc Natl Acad Sci USA 106(33):14075–14079. doi:10.1073/pnas.0906791106
Yuen EY, Liu W, Karatsoreos IN, Ren Y, Feng J, McEwen BS, Yan Z (2011) Mechanisms for acute stress-induced enhancement of glutamatergic transmission and working memory. Mol Psychiatry 16(2):156–170. doi:10.1038/mp.2010.50
Zhang H, Etherington LA, Hafner AS, Belelli D, Coussen F, Delagrange P, Chaouloff F, Spedding M, Lambert JJ, Choquet D, Groc L (2013) Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule. Mol Psychiatry 18(4):471–484. doi:10.1038/mp.2012.80
Zhou M, Hoogenraad CC, Joëls M, Krugers HJ (2012) Combined β-adrenergic and corticosteroid receptor activation regulates AMPA receptor function in hippocampal neurons. J Psychopharmacol 26(4):516–524
Zohar J, Sonnino R, Juven-Wetzler A, Cohen H (2009) Can posttraumatic stress disorder be prevented? CNS Spectr 14(1 Suppl 1):44–51
Acknowledgments
This work was supported by grants from INSERM and Paris Descartes University. DC was supported by a fellowship from the French Ministère de l’Education Nationale. MR had a financial support from Servier.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Caudal, D., Rame, M., Jay, T.M. et al. Dynamic Regulation of AMPAR Phosphorylation In Vivo Following Acute Behavioral Stress. Cell Mol Neurobiol 36, 1331–1342 (2016). https://doi.org/10.1007/s10571-016-0332-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-016-0332-9