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Loss of Phenotype of Parvalbumin Interneurons in Rat Prefrontal Cortex Is Involved in Antidepressant- and Propsychotic-Like Behaviors Following Acute and Repeated Ketamine Administration

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Abstract

Accumulating evidence has demonstrated that single subanesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant-like effects. Nevertheless, repeated subanesthetic doses of ketamine produce psychosis-like effects with dysfunction of parvalbumin (PV) interneurons. We hypothesized that PV interneurons play an important role in the antidepressant-like actions of ketamine, and different changes in PV interneurons occur with the antidepressant-like and propsychotic-like effects of ketamine. To test this hypothesis, ketamine’s antidepressant-like effects were evaluated by the forced swimming test. Ketamine-induced stereotyped behaviors and hyperactivity actions and the function of PV interneurons were also assessed. We demonstrated that an acute dose of 10 mg/kg ketamine induced significant antidepressant-like effects and reduced the levels of PV and the gamma-aminobutyric acid (GABA)-producing enzyme GAD67 in the rat prefrontal cortex. Moreover, inhibition of ketamine-induced loss of PV by apocynin blocked these antidepressant-like effects. Repeated administration of 30 mg/kg ketamine elicited stereotyped behaviors and hyperactivity actions as well as a longer duration of PV and GAD67 loss, higher brain glutamate levels, and lower brain GABA levels than acute single dose of ketamine. Our results reveal that the loss of phenotype of PV interneurons in the prefrontal cortex contributes to the antidepressant-like actions and is also involved in the propsychotic-like behaviors following acute and repeated ketamine administration, which may be partially mediated by the disinhibition of glutamate signaling. The different degrees and durations of the actions on PV interneurons produced by the two regimens of ketamine may partly underline the behavioral variance between the antidepressant- and propsychotic-like effects.

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References

  1. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE, Wang PS (2003) The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 289:3095–3105

    Article  PubMed  Google Scholar 

  2. Thase ME, Haight BR, Richard N, Rockett CB, Mitton M, Modell JG, VanMeter S, Harriett AE, Wang Y (2005) Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. J Clin Psychiatry 66:974–981

    Article  CAS  PubMed  Google Scholar 

  3. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856–864

    Article  CAS  PubMed  Google Scholar 

  4. Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, Luckenbaugh DA (2012) Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry 71:939–946

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Cornwell BR, Salvadore G, Furey M, Marquardt CA, Brutsche NE, Grillon C, Zarate CA Jr (2012) Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression. Biol Psychiatry 72(7):555–561

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Ibrahim L, Diazgranados N, Franco-Chaves J, Brutsche N, Henter ID, Kronstein P, Moaddel R, Wainer I, Luckenbaugh DA, Manji HK, Zarate CA Jr (2012) Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study. Neuropsychopharmacology 37:1526–1533

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK (2008) Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 63:349–352

    Article  CAS  PubMed  Google Scholar 

  8. Beurel E, Song L, Jope RS (2011) Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 16:1068–1070

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM, Andreazza AC, Stertz L, Fries GR, Gavioli EC, Kapczinski F, Quevedo J (2008) Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 32:140–144

    Article  CAS  PubMed  Google Scholar 

  10. Koike H, Iijima M, Chaki S (2011) Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 224:107–111

    Article  CAS  PubMed  Google Scholar 

  11. Moghaddam B, Adams B, Verma A, Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 17:2921–2927

    CAS  PubMed  Google Scholar 

  12. Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA (2003) Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 117:697–706

    Article  CAS  PubMed  Google Scholar 

  13. Razoux F, Garcia R, Lena I (2007) Ketamine, at a dose that disrupts motor behavior and latent inhibition, enhances prefrontal cortex synaptic efficacy and glutamate release in the nucleus accumbens. Neuropsychopharmacology 32:719–727

    Article  CAS  PubMed  Google Scholar 

  14. Gunduz-Bruce H (2009) The acute effects of NMDA antagonism: from the rodent to the human brain. Brain Res Rev 60:279–286

    Article  CAS  PubMed  Google Scholar 

  15. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G, Duman RS (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69:754–761

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Berdel B, Morys J (2000) Expression of calbindin-D28k and parvalbumin during development of rat’s basolateral amygdaloid complex. Int J Dev Neurosci 18:501–513

    Article  CAS  PubMed  Google Scholar 

  18. Lewis DA, Hashimoto T, Volk DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6:312–324

    Article  CAS  PubMed  Google Scholar 

  19. Sohal VS, Zhang F, Yizhar O, Deisseroth K (2009) Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459:698–702

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Wilson FA, O'Scalaidhe SP, Goldman-Rakic PS (1994) Functional synergism between putative gamma-aminobutyrate-containing neurons and pyramidal neurons in prefrontal cortex. Proc Natl Acad Sci U S A 91:4009–4013

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Povysheva NV, Gonzalez-Burgos G, Zaitsev AV, Kroner S, Barrionuevo G, Lewis DA, Krimer LS (2006) Properties of excitatory synaptic responses in fast-spiking interneurons and pyramidal cells from monkey and rat prefrontal cortex. Cereb Cortex 16:541–552

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Quibell R, Prommer EE, Mihalyo M, Twycross R, Wilcock A (2011) Ketamine*. J Pain Symptom Manag 41:640–649

    Article  CAS  Google Scholar 

  24. Vosoughin M, Mohammadi S, Dabbagh A (2012) Intravenous ketamine compared with diclofenac suppository in suppressing acute postoperative pain in women undergoing gynecologic laparoscopy. J Anesth 26:732–737

    Article  PubMed  Google Scholar 

  25. Krystal JH, Sanacora G, Duman RS (2013) Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 73:1133–1141

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Behrens MM, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, Dugan LL (2007) Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 318:1645–1647

    Article  CAS  PubMed  Google Scholar 

  27. Noda Y, Mouri A, Waki Y, Nabeshima T (2009) Development of animal models for schizophrenia based on clinical evidence: expectation for psychiatrists. Nihon Shinkei Seishin Yakurigaku Zasshi 29:47–53

    CAS  PubMed  Google Scholar 

  28. de Oliveira L, Fraga DB, De Luca RD, Canever L, Ghedim FV, Matos MP, Streck EL, Quevedo J, Zugno AI (2011) Behavioral changes and mitochondrial dysfunction in a rat model of schizophrenia induced by ketamine. Metab Brain Dis 26:69–77

    Article  PubMed  Google Scholar 

  29. Becker A, Peters B, Schroeder H, Mann T, Huether G, Grecksch G (2003) Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:687–700

    Article  CAS  PubMed  Google Scholar 

  30. Becker A, Grecksch G (2004) Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Test of predictive validity. Prog Neuropsychopharmacol Biol Psychiatry 28:1267–1277

    Article  CAS  PubMed  Google Scholar 

  31. Keilhoff G, Becker A, Grecksch G, Wolf G, Bernstein HG (2004) Repeated application of ketamine to rats induces changes in the hippocampal expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in human schizophrenia. Neuroscience 126:591–598

    Article  CAS  PubMed  Google Scholar 

  32. Tomiya M, Fukushima T, Kawai J, Aoyama C, Mitsuhashi S, Santa T, Imai K, Toyo'oka T (2006) Alterations of plasma and cerebrospinal fluid glutamate levels in rats treated with the N-methyl-D-aspartate receptor antagonist, ketamine. Biomed Chromatogr 20:628–633

    Article  CAS  PubMed  Google Scholar 

  33. Rushforth SL, Steckler T, Shoaib M (2011) Nicotine improves working memory span capacity in rats following sub-chronic ketamine exposure. Neuropsychopharmacology 36:2774–2781

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Chaviaras S, Mak P, Ralph D, Krishnan L, Broadbear JH (2010) Assessing the antidepressant-like effects of carbetocin, an oxytocin agonist, using a modification of the forced swimming test. Psychopharmacology (Berlin) 210:35–43

    Article  CAS  Google Scholar 

  35. Carrier N, Kabbaj M (2013) Sex differences in the antidepressant-like effects of ketamine. Neuropharmacology 70:27–34

    Article  CAS  PubMed  Google Scholar 

  36. Huang NK, Wan FJ, Tseng CJ, Tung CS (1997) Amphetamine induces hydroxyl radical formation in the striatum of rats. Life Sci 61:2219–2229

    Article  CAS  PubMed  Google Scholar 

  37. Zuo DY, Wu YL, Yao WX, Cao Y, Wu CF, Tanaka M (2007) Effect of MK-801 and ketamine on hydroxyl radical generation in the posterior cingulate and retrosplenial cortex of free-moving mice, as determined by in vivo microdialysis. Pharmacol Biochem Behav 86:1–7

    Article  CAS  PubMed  Google Scholar 

  38. Zhang Y, Behrens MM, Lisman JE (2008) Prolonged exposure to NMDAR antagonist suppresses inhibitory synaptic transmission in prefrontal cortex. J Neurophysiol 100:959–965

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Lodge DJ, Behrens MM, Grace AA (2009) A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia. J Neurosci 29:2344–2354

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Turner CP, DeBenedetto D, Ware E, Stowe R, Lee A, Swanson J, Walburg C, Lambert A, Lyle M, Desai P, Liu C (2010) Postnatal exposure to MK801 induces selective changes in GAD67 or parvalbumin. Exp Brain Res 201:479–488

    Article  CAS  PubMed  Google Scholar 

  41. Aoyama T, Hida K, Kuroda S, Seki T, Yano S, Shichinohe H, Iwasaki Y (2008) Edaravone (MCI-186) scavenges reactive oxygen species and ameliorates tissue damage in the murine spinal cord injury model. Neurol Med Chir (Tokyo) 48:539–545

    Article  Google Scholar 

  42. Choi SR, Roh DH, Yoon SY, Kang SY, Moon JY, Kwon SG, Choi HS, Han HJ, Beitz AJ, Oh SB, Lee JH (2013) Spinal sigma-1 receptors activate NADPH oxidase 2 leading to the induction of pain hypersensitivity in miceand mechanical allodynia in neuropathic rats. Pharmacol Res

  43. Zhang R, Ran HH, Peng L, Xu F, Sun JF, Zhang LN, Fan YY, Peng L, Cui G (2014) Mitochondrial regulation of NADPH oxidase in hindlimb unweighting rat cerebral arteries. PLoS One 9:e95916

    Article  PubMed Central  PubMed  Google Scholar 

  44. Romano-Silva MA, Ribeiro-Santos R, Ribeiro AM, Gomez MV, Diniz CR, Cordeiro MN, Diniz CR, Cordeiro MN, Brammer MJ (1993) Rat cortical synaptosomes have more than one mechanism for Ca2+ entry linked to rapid glutamate release studies using the Phoneutria nigriventer toxin PhTX2 and potassium depolarization. Biochem J 296(Pt 2):313–319

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Pinheiro AC, da Silva AJ, Prado MA, Cordeiro Mdo N, Richardson M, Batista MC, de Castro Junior CJ, Massensini AR, Guatimosim C, Romano-Silva MA, Kushmerick C, Gomez MV (2009) Phoneutria spider toxins block ischemia-induced glutamate release, neuronal death, and loss of neurotransmission in hippocampus. Hippocampus 19:1123–1129

    Article  CAS  PubMed  Google Scholar 

  46. Krishnan V, Nestler EJ (2011) Animal models of depression: molecular perspectives. Curr Top Behav Neurosci 7:121–147

    Article  PubMed Central  PubMed  Google Scholar 

  47. Berton O, Hahn CG, Thase ME (2012) Are we getting closer to valid translational models for major depression? Science 338:75–79

    Article  CAS  PubMed  Google Scholar 

  48. Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G (2012) Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 62:35–41

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Beurel E, Song L, Jope RS (2011) Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 16:1068–1070

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475:91–95

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Monteggia LM, Gideons E, Kavalali ET (2013) The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine. Biol Psychiatry 73:1199–1203

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Dwyer JM, Duman RS (2013) Activation of mammalian target of rapamycin and synaptogenesis: role in the actions of rapid-acting antidepressants. Biol Psychiatry 73:1189–1198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Xi D, Zhang W, Wang HX, Stradtman GG, Gao WJ (2009) Dizocilpine (MK-801) induces distinct changes of N-methyl-D-aspartic acid receptor subunits in parvalbumin-containing interneurons in young adult rat prefrontal cortex. Int J Neuropsychopharmacol 12:1395–1408

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Razoux F, Garcia R, Léna I (2007) Ketamine, at a dose that disrupts motor behavior and latent inhibition, enhances prefrontal cortex synaptic efficacy and glutamate release in the nucleus accumbens. Neuropsychopharmacology 32:719–727

    Article  CAS  PubMed  Google Scholar 

  56. Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA (2003) Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 117:697–706

    Article  CAS  PubMed  Google Scholar 

  57. Zhang ZJ, Reynolds GP (2002) A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 55:1–10

    Article  PubMed  Google Scholar 

  58. Zadrozna M, Nowak B, Lason-Tyburkiewicz M, Wolak M, Sowa-Kucma M, Papp M, Ossowska G, Pilc A, Nowak G (2011) Different pattern of changes in calcium binding proteins immunoreactivity in the medial prefrontal cortex of rats exposed to stress models of depression. Pharmacol Rep 63:1539–1546

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (No. 30872424 and 81271216). The authors thank the Research Institute of Nephrology of Jinling Hospital for the free use of the laboratories. They also thank Ming-chao Zhang and Gen-bao Feng for their technical assistance.

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Authors and Affiliations

  1. Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China

    ZhiQiang Zhou, GuangFen Zhang, XiaoMin Li, XiaoYu Liu, Nan Wang, LiLi Qiu, WenXue Liu & JianJun Yang

  2. Department of Anesthesiology, University of Virginia, Charlottesville, VA, USA

    ZhiYi Zuo

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  1. ZhiQiang Zhou
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  2. GuangFen Zhang
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  3. XiaoMin Li
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Correspondence to ZhiYi Zuo or JianJun Yang.

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ZhiQiang Zhou and GuangFen Zhang contributed equally to this work.

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Zhou, Z., Zhang, G., Li, X. et al. Loss of Phenotype of Parvalbumin Interneurons in Rat Prefrontal Cortex Is Involved in Antidepressant- and Propsychotic-Like Behaviors Following Acute and Repeated Ketamine Administration. Mol Neurobiol 51, 808–819 (2015). https://doi.org/10.1007/s12035-014-8798-2

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