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Alteration by p11 of mGluR5 localization regulates depression-like behaviors

Molecular Psychiatry volume 20, pages 1546–1556 (2015)Cite this article

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Abstract

Mood disorders and antidepressant therapy involve alterations of monoaminergic and glutamatergic transmission. The protein S100A10 (p11) was identified as a regulator of serotonin receptors, and it has been implicated in the etiology of depression and in mediating the antidepressant actions of selective serotonin reuptake inhibitors. Here we report that p11 can also regulate depression-like behaviors via regulation of a glutamatergic receptor in mice. p11 directly binds to the cytoplasmic tail of metabotropic glutamate receptor 5 (mGluR5). p11 and mGluR5 mutually facilitate their accumulation at the plasma membrane, and p11 increases cell surface availability of the receptor. Whereas p11 overexpression potentiates mGluR5 agonist-induced calcium responses, overexpression of mGluR5 mutant, which does not interact with p11, diminishes the calcium responses in cultured cells. Knockout of mGluR5 or p11 specifically in glutamatergic neurons in mice causes depression-like behaviors. Conversely, knockout of mGluR5 or p11 in GABAergic neurons causes antidepressant-like behaviors. Inhibition of mGluR5 with an antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), induces antidepressant-like behaviors in a p11-dependent manner. Notably, the antidepressant-like action of MPEP is mediated by parvalbumin-positive GABAergic interneurons, resulting in a decrease of inhibitory neuronal firing with a resultant increase of excitatory neuronal firing. These results identify a molecular and cellular basis by which mGluR5 antagonism achieves its antidepressant-like activity.

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References

  1. Belmaker RH, Agam G . Major depressive disorder. N Engl J Med 2008; 358: 55–68.

    Article  CAS  PubMed  Google Scholar 

  2. Svenningsson P, Kim Y, Warner-Schmidt J, Oh YS, Greengard P . p11 and its role in depression and therapeutic responses to antidepressants. Nat Rev Neurosci 2013; 14: 673–680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M et al. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 2006; 311: 77–80.

    Article  CAS  PubMed  Google Scholar 

  4. Warner-Schmidt JL, Flajolet M, Maller A, Chen EY, Qi H, Svenningsson P et al. Role of p11 in cellular and behavioral effects of 5-HT4 receptor stimulation. J Neurosci 2009; 29: 1937–1946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Alexander B, Warner-Schmidt J, Eriksson T, Tamminga C, Arango-Lievano M, Ghose S et al. Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens. Sci Transl Med 2010; 2: 54ra76.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Oh YS, Gao P, Lee KW, Ceglia I, Seo JS, Zhang X et al. SMARCA3, a chromatin-remodeling factor, is required for p11-dependent antidepressant action. Cell 2013; 152: 831–843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Schmidt EF, Warner-Schmidt JL, Otopalik BG, Pickett SB, Greengard P, Heintz N . Identification of the cortical neurons that mediate antidepressant responses. Cell 2012; 149: 1152–1163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Egeland M, Warner-Schmidt J, Greengard P, Svenningsson P . Neurogenic effects of fluoxetine are attenuated in p11 (S100A10) knockout mice. Biol Psychiatry 2010; 67: 1048–1056.

    Article  CAS  PubMed  Google Scholar 

  9. Conn PJ, Pin JP . Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 1997; 37: 205–237.

    Article  CAS  PubMed  Google Scholar 

  10. Chaki S, Ago Y, Palucha-Paniewiera A, Matrisciano F, A Pilc . mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants. Neuropharmacology 2013; 66: 40–52.

    Article  CAS  PubMed  Google Scholar 

  11. Goeldner C, Ballard TM, Knoflach F, Wichmann J, Gatti S, Umbricht D . Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target. Neuropharmacology 2013; 64: 337–346.

    Article  CAS  PubMed  Google Scholar 

  12. Palucha-Poniewiera A, Wieronska JM, Branski P, Burnat G, Chruscicka B, Pilc A . Is the mGlu5 receptor a possible target for new antidepressant drugs? Pharmacol Rep 2013; 65: 1506–1511.

    Article  CAS  PubMed  Google Scholar 

  13. Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P . Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci USA 2011; 108: 9262–9267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu J, Zhu Y, Contractor A, Heinemann SF . mGluR5 has a critical role in inhibitory learning. J Neurosci 2009; 29: 3676–3684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tatarczynska E, Klodzinska A, Chojnacka-Wojcik E, Palucha A, Gasparini F, Kuhn R et al. Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharmacol 2001; 132: 1423–1430.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li X, Need AB, Baez M, Witkin JM . Metabotropic glutamate 5 receptor antagonism is associated with antidepressant-like effects in mice. J Pharmacol Exp Ther 2006; 319: 254–259.

    Article  CAS  PubMed  Google Scholar 

  17. Iijima M, Fukumoto K, Chaki S . Acute and sustained effects of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test. Behav Brain Res 2012; 235: 287–292.

    Article  CAS  PubMed  Google Scholar 

  18. Wang H, Westin L, Nong Y, Birnbaum S, Bendor J, Brismar H et al. Norbin is an endogenous regulator of metabotropic glutamate receptor 5 signaling. Science 2009; 326: 1554–1557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Joseph G, Pick E . "Peptide walking" is a novel method for mapping functional domains in proteins. Its application to the Rac1-dependent activation of NADPH oxidase. J Biol Chem 1995; 270: 29079–29082.

    Article  CAS  PubMed  Google Scholar 

  20. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329: 959–964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chang JC, Tomlinson ID, Warnement MR, Ustione A, Carneiro AM, Piston DW et al. Single molecule analysis of serotonin transporter regulation using antagonist-conjugated quantum dots reveals restricted, p38 MAPK-dependent mobilization underlying uptake activation. J Neurosci 2012; 32: 8919–8929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Izumi J, Washizuka M, Hayashi-Kuwabara Y, Yoshinaga K, Tanaka Y, Ikeda Y et al. Evidence for a depressive-like state induced by repeated saline injections in Fischer 344 rats. Pharmacol Biochem Behav 1997; 57: 883–888.

    Article  CAS  PubMed  Google Scholar 

  23. Strekalova T, Spanagel R, Bartsch D, Henn FA, Gass P . Stress-induced anhedonia in mice is associated with deficits in forced swimming and exploration. Neuropsychopharmacology 2004; 29: 2007–2017.

    Article  PubMed  Google Scholar 

  24. Royer S, Zemelman BV, Losonczy A, Kim J, Chance F, Magee JC et al. Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition. Nat Neurosci 2012; 15: 769–775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Anikeeva P, Andalman AS, Witten I, Warden M, Goshen I, Grosenick L et al. Optetrode: a multichannel readout for optogenetic control in freely moving mice. Nat Neurosci 2012; 15: 163–170.

    Article  CAS  Google Scholar 

  26. Wilson FA, O’Scalaidhe SP, Goldman-Rakic PS . Functional synergism between putative gamma-aminobutyrate-containing neurons and pyramidal neurons in prefrontal cortex. Proc Natl Acad Sci USA 1994; 91: 4009–4013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Connors BW, Gutnick MJ . Intrinsic firing patterns of diverse neocortical neurons. Trends Neurosci 1990; 13: 99–104.

    Article  CAS  PubMed  Google Scholar 

  28. Homayoun H, Moghaddam B . NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 2007; 27: 11496–11500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Girard C, Tinel N, Terrenoire C, Romey G, Lazdunski M, Borsotto M . p11, an annexin II subunit, an auxiliary protein associated with the background K+ channel, TASK-1. EMBO J 2002; 21: 4439–4448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. van de Graaf SF, Hoenderop JG, Gkika D, Lamers D, Prenen J, Rescher U et al. Functional expression of the epithelial Ca(2+) channels (TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex. EMBO J 2003; 22: 1478–1487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rezvanpour A, Phillips JM, Shaw GS . Design of high-affinity S100-target hybrid proteins. Protein Sci 2009; 18: 2528–2536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Okuse K, Malik-Hall M, Baker MD, Poon WY, Kong H, Chao MV et al. Annexin II light chain regulates sensory neuron-specific sodium channel expression. Nature 2002; 417: 653–656.

    Article  CAS  PubMed  Google Scholar 

  33. Donier E, Rugiero F, Okuse K, Wood JN . Annexin II light chain p11 promotes functional expression of acid-sensing ion channel ASIC1a. J Biol Chem 2005; 280: 38666–38672.

    Article  CAS  PubMed  Google Scholar 

  34. Lopez-Bendito G, Shigemoto R, Fairen A, Lujan R . Differential distribution of group I metabotropic glutamate receptors during rat cortical development. Cereb Cortex 2002; 12: 625–638.

    Article  CAS  PubMed  Google Scholar 

  35. van Hooft JA, Giuffrida R, Blatow M, Monyer H . Differential expression of group I metabotropic glutamate receptors in functionally distinct hippocampal interneurons. J Neurosci 2000; 20: 3544–3551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sun QQ, Zhang Z, Jiao Y, Zhang C, Szabo G, Erdelyi F . Differential metabotropic glutamate receptor expression and modulation in two neocortical inhibitory networks. J Neurophysiol 2009; 101: 2679–2692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Egeland M, Warner-Schmidt J, Greengard P, Svenningsson P . Co-expression of serotonin 5-HT(1B) and 5-HT(4) receptors in p11 containing cells in cerebral cortex, hippocampus, caudate-putamen and cerebellum. Neuropharmacology 2011; 61: 442–450.

    Article  CAS  PubMed  Google Scholar 

  38. Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O’Shea DJ et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 2011; 477: 171–178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lapidus KA, Soleimani L, Murrough JW . Novel glutamatergic drugs for the treatment of mood disorders. Neuropsychiatr Dis Treat 2013; 9: 1101–1112.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805–809.

    Article  CAS  PubMed  Google Scholar 

  41. Dulawa SC, Hen R . Recent advances in animal models of chronic antidepressant effects: the novelty-induced hypophagia test. Neurosci Biobehav Rev 2005; 29: 771–783.

    Article  CAS  PubMed  Google Scholar 

  42. Koike H, Fukumoto K, Iijima M, Chaki S . Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression. Behav Brain Res 2013; 238: 48–52.

    Article  CAS  PubMed  Google Scholar 

  43. Rudy B, Fishell G, Lee S, Hjerling-Leffler J . Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev Neurobiol 2011; 71: 45–61.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Chu Z, Hablitz JJ . Activation of group I mGluRs increases spontaneous IPSC frequency in rat frontal cortex. J Neurophysiol 1998; 80: 621–627.

    Article  CAS  PubMed  Google Scholar 

  45. Govindaiah G, Cox CL . Metabotropic glutamate receptors differentially regulate GABAergic inhibition in thalamus. J Neurosci 2006; 26: 13443–13453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Campanac E, Gasselin C, Baude A, Rama S, Ankri N, Debanne D . Enhanced intrinsic excitability in basket cells maintains excitatory-inhibitory balance in hippocampal circuits. Neuron 2013; 77: 712–722.

    Article  CAS  PubMed  Google Scholar 

  47. Elliott R, Baker SC, Rogers RD, O’Leary DA, Paykel ES, Frith CD et al. Prefrontal dysfunction in depressed patients performing a complex planning task: a study using positron emission tomography. Psychol Med 1997; 27: 931–942.

    Article  CAS  PubMed  Google Scholar 

  48. Disner SG, Beevers CG, Haigh EA, Beck AT . Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci 2011; 12: 467–477.

    Article  CAS  PubMed  Google Scholar 

  49. Covington HE 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci 2010; 30: 16082–16090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hamani C, Diwan M, Macedo CE, Brandao ML, Shumake J, Gonzalez-Lima F et al. Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats. Biol Psychiatry 2010; 67: 117–124.

    Article  PubMed  Google Scholar 

  51. Romano C, Sesma MA, McDonald CT, O’Malley K, Van den Pol AN, Olney JW . Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain. J Comp Neurol 1995; 355: 455–469.

    Article  CAS  PubMed  Google Scholar 

  52. Warner-Schmidt JL, Schmidt EF, Marshall JJ, Rubin AJ, Arango-Lievano M, Kaplitt MG et al. Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. Proc Natl Acad Sci USA 2012; 109: 11360–11365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Svenningsson P, Greengard P . p11 (S100A10)—an inducible adaptor protein that modulates neuronal functions. Curr Opin Pharmacol 2007; 7: 27–32.

    Article  CAS  PubMed  Google Scholar 

  54. Compan V, Zhou M, Grailhe R, Gazzara RA, Martin R, Gingrich J et al. Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knock-out mice. J Neurosci 2004; 24: 412–419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Coryell MW, Wunsch AM, Haenfler JM, Allen JE, Schnizler M, Ziemann AE et al. Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior. J Neurosci 2009; 29: 5381–5388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Warner-Schmidt JL, Chen EY, Zhang X, Marshall JJ, Morozov A, Svenningsson P et al. A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry 2010; 68: 528–535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Brakeman PR, Lanahan AA, O’Brien R, Roche K, Barnes CA, Huganir RL et al. Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 1997; 386: 284–288.

    Article  CAS  PubMed  Google Scholar 

  58. Choi KY, Chung S, Roche KW . Differential binding of calmodulin to group I metabotropic glutamate receptors regulates receptor trafficking and signaling. J Neurosci 2011; 31: 5921–5930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kitano J, Yamazaki Y, Kimura K, Masukado T, Nakajima Y, Nakanishi S . Tamalin is a scaffold protein that interacts with multiple neuronal proteins in distinct modes of protein-protein association. J Biol Chem 2003; 278: 14762–14768.

    Article  CAS  PubMed  Google Scholar 

  60. Rietschel M, Mattheisen M, Frank J, Treutlein J, Degenhardt F, Breuer R et al. Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression. Biol Psychiatry 2010; 68: 578–585.

    CAS  PubMed  Google Scholar 

  61. Carroll FI . Antagonists at metabotropic glutamate receptor subtype 5: structure activity relationships and therapeutic potential for addiction. Ann NY Acad Sci 2008; 1141: 221–232.

    Article  CAS  PubMed  Google Scholar 

  62. Gregory KJ, Dong EN, Meiler J, Conn PJ . Allosteric modulation of metabotropic glutamate receptors: structural insights and therapeutic potential. Neuropharmacology 2011; 60: 66–81.

    Article  CAS  PubMed  Google Scholar 

  63. Yin S, Niswender CM . Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications. Cell Signal 2014; 26: 2284–2297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Piers TM, Kim DH, Kim BC, Regan P, Whitcomb DJ, Cho K . Translational Concepts of mGluR5 in Synaptic Diseases of the Brain. Front Pharmacol 2012; 3: 199.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Krueger DD, Bear MF . Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu Rev Med 2011; 62: 411–429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bezard E, Pioli EY, Li Q, Girard F, Mutel V, Keywood C et al. The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model. Mov Disord 2014; 29: 1074–1079.

    Article  CAS  PubMed  Google Scholar 

  67. Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ . Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci 2000; 20: 7871–7879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Rosenbrock H, Kramer G, Hobson S, Koros E, Grundl M, Grauert M et al. Functional interaction of metabotropic glutamate receptor 5 and NMDA-receptor by a metabotropic glutamate receptor 5 positive allosteric modulator. Eur J Pharmacol 2010; 639: 40–46.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr H Wang for discussion and sharing materials. We thank Dr A Contractor for providing us floxed mGluR5 mice. We thank C Hsaio for assistance with animal maintenance. We acknowledge R Norinsky and the Rockefeller University Transgenics Services Laboratory for their excellent in vitro fertilization services, and H Zebroski III and the Rockefeller University Proteomics Resource Center for peptide synthesis. We thank Drs K Thomas and A North at the Rockefeller University Bio-imaging Resource Center for their help with fluorescent microscopy. We acknowledge E Griggs for graphics. This work was supported by DOD/USAMRMC Grants W81XWH-09-1-0392 (to YK), W81XWH-10-1-0691 (to MF) and W81XWH-09-1-0402 (to PG); NIH Grants MH074866 (to PG) and DA010044 (to PG); the Fisher Center for Alzheimer’s Research Foundation (to PG); The JPB Foundation (to PG); Swedish Research Council and the Erling-Persson Family Foundation (to AA); and the National Leading Research Laboratory Program, 2011-0028772 (to DK).

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  1. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA

    K-W Lee, J C Chang, Y-S Oh, B Amreen, J Gresack, M Flajolet, Y Kim & P Greengard

  2. Department of Women’s and Children’s Health, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden

    L Westin & A Aperia

  3. Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea

    J Kim & D Kim

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Lee, KW., Westin, L., Kim, J. et al. Alteration by p11 of mGluR5 localization regulates depression-like behaviors. Mol Psychiatry 20, 1546–1556 (2015). https://doi.org/10.1038/mp.2015.132

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