Advertisement

Selective Knockdown of TASK3 Potassium Channel in Monoamine Neurons: a New Therapeutic Approach for Depression

  • M. Neus Fullana
  • Albert Ferrés-Coy
  • Jorge E. Ortega
  • Esther Ruiz-Bronchal
  • Verónica Paz
  • J. Javier Meana
  • Francesc Artigas
  • Analia Bortolozzi
Article

Abstract

Current pharmacological treatments for major depressive disorder (MDD) are severely compromised by both slow action and limited efficacy. RNAi strategies have been used to evoke antidepressant-like effects faster than classical drugs. Using small interfering RNA (siRNA), we herein show that TASK3 potassium channel knockdown in monoamine neurons induces antidepressant-like responses in mice. TASK3-siRNAs were conjugated to cell-specific ligands, sertraline (Ser) or reboxetine (Reb), to promote their selective accumulation in serotonin (5-HT) and norepinephrine (NE) neurons, respectively, after intranasal delivery. Following neuronal internalization of conjugated TASK3-siRNAs, reduced TASK3 mRNA and protein levels were found in the brainstem 5-HT and NE cell groups. Moreover, Ser-TASK3-siRNA induced robust antidepressant-like behaviors, enhanced the hippocampal plasticity, and potentiated the fluoxetine-induced increase on extracellular 5-HT. Similar responses, yet of lower magnitude, were detected for Reb-TASK3-siRNA. These findings provide substantial support for TASK3 as a potential target, and RNAi-based strategies as a novel therapeutic approach to treat MDD.

Keywords

RNAi Depression New antidepressant target K2P channel Intranasal delivery 

Notes

Acknowledgements

We thank María Calvo, Elisenda Coll, and Anna Bosch for outstanding technical support in the confocal microscopy unit (CCiT-UB); and Mireia Galofré and Letizia Campa for their outstanding technical assistance. We also thank J Pablo Salvador and Núria Pascual for the TASK3 antibody production and purification (Institut de Quimica Avançada de Catalunya, CSIC; Parc Cientific de Barcelona, UB; and CIBER in Bioengineering, Biomaterials, and Nanomedicine), and to Nlife Therapeutics S.L. for advice on the design of conjugated siRNA molecules.

Funding

This work was supported by the following grants: SAF2015-68346-P (F.A.); SAF2013-48586-R (J.M.); SAF2016-75797-R (A.B.); Retos-Colaboración Subprograms RTC-2014-2812-1 and RTC-2015-3309-1 (A.B.); Ministry of Economy and Competitiveness (MINECO)—European Regional Development Fund (ERDF), UE; PI13/01390, Instituto de Salud Carlos III co-financed by ERDF (A.B.); IT616-13 Basque Government—ERDF (J.M.); 20003 NARSAD Independent Investigator (A.B.); and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). CERCA Programme/Generalitat de Catalunya is also acknowledged. M.N.F. and A.F-C. are recipients of a fellowship from the Spanish Ministry of Education, Culture and Sport.

Compliance with Ethical Standards

Conflict of Interest

F.A. has received consulting honoraria on antidepressant drugs from Lundbeck and he has been PI of grants from Lundbeck. A.B. has been PI of grants from Nlife Therapeutics. S.L., F.A., and A.B. are coauthors of the patent WO/2011/131693 for the siRNA and ASO (antisense oligonucleotides) molecules and the targeting approach related to this work. The rest of authors declare no competing financial interest.

Supplementary material

12035_2018_1288_MOESM1_ESM.docx (2.5 mb)
ESM 1 (DOCX 2522 kb)

References

  1. 1.
    Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C et al (2012) Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the global burden of disease study 2010. Lancet 380:2197–2223CrossRefPubMedGoogle Scholar
  2. 2.
    Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE et al (2013) Global burden of disease attributable to mental and substance use disorders: findings from the global burden of disease study 2010. Lancet 382:1575–1586CrossRefPubMedGoogle Scholar
  3. 3.
    Global Burden of Disease Study 2013 Collaborators (2015) Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the global burden of disease study 2013. Lancet 386:743–800CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH et al (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163:28–40CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA et al (2006) Medication augmentation after the failure of SSRIs for depression. N Engl J Med 354:1243–1252CrossRefPubMedGoogle Scholar
  6. 6.
    Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D et al (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163:1905–1917CrossRefPubMedGoogle Scholar
  7. 7.
    Artigas F, Bortolozzi A (2017) Therapeutic potential of conjugated siRNAs for the treatment of major depressive disorder. Neuropsychopharmacol 42:371CrossRefGoogle Scholar
  8. 8.
    Artigas F, Celada P, Bortolozzi A (2018) Can we increase the speed and efficacy of antidepressant treatments? Part II Glutamatergic and RNA interference strategies. Eur Neuropsychopharmacol 28:457–482.  https://doi.org/10.1016/j.euroneuro.2018.01.005 CrossRefPubMedGoogle Scholar
  9. 9.
    Bortolozzi A, Castañé A, Semakova J, Santana N, Alvarado G, Cortés R, Ferrés-Coy A, Fernández G et al (2012) Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects. Mol Psychiatry 17:612–623CrossRefPubMedGoogle Scholar
  10. 10.
    Ferrés-Coy A, Galofré M, Pilar-Cuéllar F, Vidal R, Paz V, Ruiz-Bronchal E, Campa L, Pazos Á et al (2016) Therapeutic antidepressant potential of a conjugated siRNA silencing the serotonin transporter after intranasal administration. Mol Psychiatry 21:328–338CrossRefPubMedGoogle Scholar
  11. 11.
    Ferrés-Coy A, Santana N, Castañé A, Cortés R, Carmona MC, Toth M, Montefeltro A, Artigas F et al (2013) Acute 5-HT1A autoreceptor knockdown increases antidepressant responses and serotonin release in stressful conditions. Psychopharmacology 225:61–74CrossRefPubMedGoogle Scholar
  12. 12.
    Ferrés-Coy A, Pilar-Cuellar F, Vidal R, Paz V, Masana M, Cortés R et al (2013) RNAi-mediated serotonin transporter suppression rapidly increases serotonergic neurotransmission and hippocampal neurogenesis. Transl Psychiatry 3:11e211CrossRefGoogle Scholar
  13. 13.
    Rajan S, Wischmeyer E, Xin Liu G, Preisig-Müller R, Daut J, Karschin A, Derst C (2000) TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histiding as pH sensor. J Biol Chem 275:16650–16657CrossRefPubMedGoogle Scholar
  14. 14.
    Bayliss DA, Barrett PQ (2008) Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact. Trends Pharmacol Sci 29:566–575CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Russo SJ, Murrough JW, Han MH, Charney DS, Nestler EJ (2012) Neurobiology of resilience. Nat Neurosci 15:1475–1484CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Borsotto M, Veyssiere J, Moha Ou Maati H, Devader C, Mazella J, Heurteaux C (2015) Targeting two-pore domain K(+) channels TREK-1 and TASK-3 for the treatment of depression: a new therapeutic concept. Br J Pharmacol 172:771–784CrossRefPubMedGoogle Scholar
  17. 17.
    Gotter AL, Santarelli VP, Doran SM, Tannenbaum PL, Kraus RL, Rosahl TW, Meziane H, Montial M et al (2011) TASK-3 as a potential antidepressant target. Brain Res 1416:69–79CrossRefPubMedGoogle Scholar
  18. 18.
    Coburn CA, Luo Y, Cui M, Wang J, Soll R, Dong J, Hu B, Lyon MA et al (2012) Discovery of a pharmacologically active antagonist of the two-pore-domain potassium channel K2P9.1 (TASK-3). Chem Med Chem 7:123–133CrossRefPubMedGoogle Scholar
  19. 19.
    Karschin C, Wischmeyer E, Preisig-Müller R, Rajan S, Derst C, Grzeschik KH, Daut J, Karschin A (2001) Expression pattern in brain of TASK-1, TASK-3, and a tandem pore domain K+ channel subunit, TASK-5, associated with the central auditory nervous system. Mol Cell Neurosci 18:632–648CrossRefPubMedGoogle Scholar
  20. 20.
    Meadows HJ, Randall AD (2001) Functional characterisation of human TASK-3, an acid-sensitive two-pore domain potassium channel. Neuropharmacology 40:551–559CrossRefPubMedGoogle Scholar
  21. 21.
    Medhurst A, Rennie G, Chapman C, Meadows H, Duckworth M, Kelsell R et al (2001) Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery. Mol Brain Res 86:101–114CrossRefPubMedGoogle Scholar
  22. 22.
    Talley EM, Solorzano G, Lei Q, Kim D, Bayliss DA (2001) CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. J Neurosci 21:7491–7505CrossRefPubMedGoogle Scholar
  23. 23.
    Marinc C, Preisig-Müller R, Prüss H, Derst C, Veh RW (2011) Immunocytochemical localization of TASK-3 (K2P 9.1) channels in monoaminergic and cholinergic neurons. Cell Mol Neurobiol 31:323–335CrossRefPubMedGoogle Scholar
  24. 24.
    Linden AM, Sandu C, Aller MI, Vekovischeva OY, Rosenberg PH, Wisden W, Korpi ER (2007) TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive functions, and reduced sensitivity to inhalation anesthetics. J Pharmacol Exp Ther 323:924–934CrossRefPubMedGoogle Scholar
  25. 25.
    Alarcón-Arís D, Recasens A, Galofré M, Carballo-Carbajal I, Zacchi N, Ruiz-Bronchal E, Pavia-Collado R, Chica R et al (2018) Selective α-synuclein knockdown in monoamine neurons by intranasal oligonucleotide delivery: potential therapy for Parkinson’s disease. Mol Ther 26:550–567CrossRefPubMedGoogle Scholar
  26. 26.
    Franklin KBJ, Paxinos G (2008) The mouse brain in stereotaxic coordinates. Academic Press, New YorkGoogle Scholar
  27. 27.
    Mateo Y, Meana JJ (1999) Determination of the somatodendritic alpha2-adrenoceptor subtype located in rat locus coeruleus that modulates cortical noradrenaline release in vivo. Eur J Pharmacol 379:53–57CrossRefPubMedGoogle Scholar
  28. 28.
    Mateo Y, Fernández-Pastor B, Meana JJ (2001) Acute and chronic effects of desipramine and clorgyline on alpha(2)-adrenoceptors regulating noradrenergic transmission in the rat brain: a dual-probe microdialysis study. Br J Pharmacol 133:1362–1370CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ortega JE, Katner J, Davis R, Wade M, Nisenbaum L, Nomikos GG, Svensson KA, Perry KW (2012) Modulation of neurotransmitter release in orexin/hypocretin-2 receptor knockout mice: a microdialysis study. J Neurosci Res 90:588–596CrossRefPubMedGoogle Scholar
  30. 30.
    Samuels BA, Hen R (2011) Novelty-suppressed feeding in the mouse. In: Gould TD (ed) Mood and anxiety related phenotypes in mice: characterization using behavioral test, Volume II. Springer, New York, pp. 107–121CrossRefGoogle Scholar
  31. 31.
    Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660CrossRefPubMedGoogle Scholar
  32. 32.
    Duman RS, Voleti B (2012) Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents. Trends Neurosci 35:47–56CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Javitch JA, Strittmatter SM, Snyder SH (1985) Differential visualization of dopamine and norepinephrine uptake sites in rat brain using [3H]mazindol autoradiography. J Neurosci 5:1513–1521CrossRefPubMedGoogle Scholar
  34. 34.
    Cortés R, Soriano E, Pazos A, Probst A, Palacios JM (1988) Autoradiography of antidepressant binding sites in the human brain: localization using [3H]imipramine and [3H]paroxetine. Neuroscience 27:473–496CrossRefPubMedGoogle Scholar
  35. 35.
    Wang JW, David DJ, Monckton JE, Battaglia F, Hen R (2008) Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci 28:1374–1384CrossRefPubMedGoogle Scholar
  36. 36.
    Brachman RA, McGowan JC, Perusini JN, Lim SC, Pham TH, Faye C et al (2016) Ketamine as a prophylactic against stress-induced depressive-like behavior. Biol Psychiatry 79:776–786CrossRefPubMedGoogle Scholar
  37. 37.
    Redrobe JP, Bourin M (1998) Dose-dependent influence of buspirone on the activities of selective serotonin reuptake inhibitors in the mouse forced swimming test. Psychopharmacology 138:198–206CrossRefPubMedGoogle Scholar
  38. 38.
    Wong EH, Sonders MS, Amara SG, Tinholt PM, Piercey MF, Hoffmann WP et al (2000) Reboxetine: a pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor. Biol Psychiatry 47:818–829CrossRefPubMedGoogle Scholar
  39. 39.
    Cryan JF, O’Leary OF, Jin SH, Friedland JC, Ouyang M, Hirsch BR et al (2004) Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors. Proc Natl Acad Sci U S A 101:8186–8891CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    O’Leary OF, Bechtholt AJ, Crowley JJ, Hill TE, Page ME, Lucki I (2007) Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test. Psychopharmacology 192:357–371CrossRefPubMedGoogle Scholar
  41. 41.
    Roni MA, Rahman S (2015) Effects of lobeline and reboxetine, fluoxetine, or bupropion combination on depression-like behaviors in mice. Pharmacol Biochem Behav 139(Pt A):1–6CrossRefPubMedGoogle Scholar
  42. 42.
    Artigas F, Romero L, de Montigny C, Blier P (1996) Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 19:378–383CrossRefPubMedGoogle Scholar
  43. 43.
    Hervás I, Artigas F (1998) Effect of fluoxetine on extracellular 5-hydroxytryptamine in rat brain. Role of 5-HT autoreceptors. Eur J Pharmacol 358:9–18CrossRefPubMedGoogle Scholar
  44. 44.
    Mateo Y, Pineda J, Meana JJ (1998) Somatodendritic alpha2-adrenoceptors in the locus coeruleus are involved in the in vivo modulation of cortical noradrenaline release by the antidepressant desipramine. J Neurochem 71:790–798CrossRefPubMedGoogle Scholar
  45. 45.
    Ortega JE, Fernández-Pastor B, Callado LF, Meana JJ (2010) In vivo potentiation of reboxetine and citalopram effect on extracellular noradrenaline in rat brain by α2-adrenoceptor antagonism. Eur Neuropsychopharmacol 20:813–822CrossRefPubMedGoogle Scholar
  46. 46.
    Washburn CP, Sirois JE, Talley EM, Guyenet PG, Bayliss DA (2002) Serotonergic raphe neurons express TASK channel transcripts and a TASK-like pH- and halothane-sensitive K+ conductance. J Neurosci 22:1256–1265CrossRefPubMedGoogle Scholar
  47. 47.
    Gordon JA, Hen R (2006) TREKing toward new antidepressants. Nat Neurosci 9:1081–1083CrossRefPubMedGoogle Scholar
  48. 48.
    Mazella J, Pétrault O, Lucas G, Deval E, Béraud-Dufour S, Gandin C, el-Yacoubi M, Widmann C et al (2010) Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol 8:e1000355CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Kennard LE, Chumbley JR, Ranatunga KM, Armstrong SJ, Veale EL, Mathie A (2005) Inhibition of the human two-pore domain potassium channel, TREK-1, by fluoxetine and its metabolite norfluoxetine. Br J Pharmacol 144:821–829CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sandoz G, Bell SC, Isacoff EY (2011) Optical probing of a dynamic membrane interaction that regulates the TREK1 channel. Proc Natl Acad Sci U S A 108:2605–2610CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Hajdu P, Ulens C, Panyi G, Tytgat J (2003) Drug- and mutagenesis-induced changes in the selectivity filter of a cardiac two-pore background K+ channel. Cardiovasc Res 58:46–54CrossRefPubMedGoogle Scholar
  52. 52.
    Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G (1998) Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity. J Neurosci 18:7394–7401CrossRefPubMedGoogle Scholar
  53. 53.
    Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD et al (2003) Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 23:8788–8799CrossRefPubMedGoogle Scholar
  54. 54.
    Lemonde S, Du L, Bakish D, Hrdina P, Albert PR (2004) Association of the C(-1019)G 5-HT1A functional promoter polymorphism with antidepressant response. Int J Neuropsychopharmacol 7:501–506CrossRefPubMedGoogle Scholar
  55. 55.
    Neff CD, Abkevich V, Packer JC, Chen Y, Potter J, Riley R et al (2009) Evidence for HTR1A and LHPP as interacting genetic risk factors in major depression. Mol Psychiatry 14:621–630CrossRefPubMedGoogle Scholar
  56. 56.
    Richardson-Jones JW, Craige CP, Guiard BP, Stephen A, Metzger KL, Kung HF, Gardier AM, Dranovsky A et al (2010) 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron 65:40–52CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Pei Q, Zetterström TS, Sprakes M, Tordera R, Sharp T (2003) Antidepressant drug treatment induces Arc gene expression in the rat brain. Neuroscience 121:975–982CrossRefPubMedGoogle Scholar
  59. 59.
    David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, Drew M, Craig DA et al (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62:479–493CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Dranovsky A, Hen R (2006) Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry 59:1136–1143CrossRefPubMedGoogle Scholar
  61. 61.
    Page ME (2003) The promises and pitfalls of reboxetine. CNS Drug Rev 9:327–342CrossRefPubMedGoogle Scholar
  62. 62.
    Sanchez C, Reines EH, Montgomery SA (2014) A comparative review of escitalopram, paroxetine, and sertraline: Are they all alike? Int Clin Psychopharmacol 29:185–196CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • M. Neus Fullana
    • 1
    • 2
    • 3
  • Albert Ferrés-Coy
    • 1
    • 2
    • 3
  • Jorge E. Ortega
    • 3
    • 4
  • Esther Ruiz-Bronchal
    • 1
    • 2
    • 3
  • Verónica Paz
    • 1
    • 2
    • 3
  • J. Javier Meana
    • 3
    • 4
  • Francesc Artigas
    • 1
    • 2
    • 3
  • Analia Bortolozzi
    • 1
    • 2
    • 3
  1. 1.Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)BarcelonaSpain
  2. 2.Department of Neurochemistry and NeuropharmacologyIIBB-CSIC (Consejo Superior de Investigaciones Científicas)BarcelonaSpain
  3. 3.Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIIIMadridSpain
  4. 4.Department of PharmacologyUniversity of Basque Country UPV/EHU and BioCruces Health Research InstituteBizkaiaSpain

Personalised recommendations