Skip to main content
SpringerLink
Log in

NOX2 Mediated-Parvalbumin Interneuron Loss Might Contribute to Anxiety-Like and Enhanced Fear Learning Behavior in a Rat Model of Post-Traumatic Stress Disorder

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Post-traumatic stress disorder (PTSD) is a common psychiatric disease following exposure to a severe traumatic event or physiological stress, yet the precise mechanisms underlying PTSD remains largely to be determined. Using an animal model of PTSD induced by a single prolonged stress (SPS), we assessed the role of hippocampal nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and parvalbumin (PV) interneurons in the development of PTSD symptoms. In the present study, behavioral tests were performed by the open field (day 13 after SPS) and fear conditioning tests (days 13 and 14 after SPS). For the interventional study, rats were chronically treated with a NADPH oxidase inhibitor apocynin either by early or delayed administration. The levels of tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, IL-10, malondialdehyde, superoxide dismutase, NOX2, 4-hydroxynonenal, and PV in the hippocampus were measured at the indicated time points. In the present study, we showed that SPS rats displayed anxiety-like and enhanced fear learning behavior, which was accompanied by the increased expressions of malondialdehyde, IL-6, NOX2, 4-hydroxynonenal, and decreased PV expression. Notably, early but not delayed treatment with apocynin reversed all these abnormalities after SPS. In conclusion, our results provided evidence that NOX2 activation in the hippocampus, at least in part, contributes to oxidative stress and neuroinflammation, which further results in PV interneuron loss and consequent PTSD symptoms in a rat model of PTSD induced by SPS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Qiu ZK, Zhang LM, Zhao N, Chen HX, Zhang YZ, Liu YQ, Mi TY, Zhou WW et al (2013) Repeated administration of AC-5216, a ligand for the 18 kDa translocator protein, improves behavioral deficits in a mouse model of post-traumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 45:40–46. doi:10.1016/j.pnpbp.2013.04.010

    Article  CAS  PubMed  Google Scholar 

  2. Gamache K, Pitman RK, Nader K (2012) Preclinical evaluation of reconsolidation blockade by clonidine as a potential novel treatment for posttraumatic stress disorder. Neuropsychopharmacology 37(13):2789–2796. doi:10.1038/npp.2012.145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ji MH, Jia M, Zhang MQ, Liu WX, Xie ZC, Wang ZY, Yang JJ (2014) Dexmedetomidine alleviates anxiety-like behaviors and cognitive impairments in a rat model of post-traumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 54:284–288. doi:10.1016/j.pnpbp.2014.06.013

    Article  CAS  PubMed  Google Scholar 

  4. Johansen JP, Cain CK, Ostroff LE, LeDoux JE (2011) Molecular mechanisms of fear learning and memory. Cell 147(3):509–524. doi:10.1016/j.cell.2011.10.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Parsons RG, Ressler KJ (2013) Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci 16(2):146–153. doi:10.1038/nn.3296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wilson CB, McLaughlin LD, Ebenezer PJ, Nair AR, Francis J (2014) Valproic acid effects in the hippocampus and prefrontal cortex in an animal model of post-traumatic stress disorder. Behav Brain Res 268:72–80. doi:10.1016/j.bbr.2014.03.029

    Article  CAS  PubMed  Google Scholar 

  7. Wilson CB, McLaughlin LD, Nair A, Ebenezer PJ, Dange R, Francis J (2013) Inflammation and oxidative stress are elevated in the brain, blood, and adrenal glands during the progression of post-traumatic stress disorder in a predator exposure animal model. PLoS One 8:e76146. doi:10.1371/journal.pone.0076146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gola H, Engler H, Sommershof A, Adenauer H, Kolassa S, Schedlowski M, Groettrup M, Elbert T et al (2013) Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells. BMC Psychiatry 13:40. doi:10.1186/1471-244X-13-40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bulut M, Selek S, Bez Y, Karababa IF, Kaya MC, Gunes M, Emhan A, Aksoy N et al (2013) Reduced PON1 enzymatic activity and increased lipid hydroperoxide levels that point out oxidative stress in generalized anxiety disorder. J Affect Disord 150(3):829–833. doi:10.1016/j.jad.2013.03.011

    Article  CAS  PubMed  Google Scholar 

  10. Zhou Z, Zhang G, Li X, Liu X, Wang N, Qiu L, Liu W, Zuo Z et al (2015) 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(2):808–819. doi:10.1007/s12035-014-8798-2

    Article  CAS  PubMed  Google Scholar 

  11. Del Pino I, García-Frigola C, Dehorter N, Brotons-Mas JR, Alvarez-Salvado E, Martínez de Lagrán M, Ciceri G, Gabaldón MV et al (2013) Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes. Neuron 79(6):1152–1168. doi:10.1016/j.neuron.2013.07.010

    Article  CAS  PubMed  Google Scholar 

  12. Wöhr M, Orduz D, Gregory P, Moreno H, Khan U, Vörckel KJ, Wolfer DP, Welzl H et al (2015) Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities. Translat Psychiatry 5:e525. doi:10.1038/tp.2015.19

    Article  CAS  Google Scholar 

  13. Verret L, Mann EO, Hang GB, Barth AM, Cobos I, Ho K, Devidze N, Masliah E et al (2012) Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149(3):708–721. doi:10.1016/j.cell.2012.02.046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yekhlef L, Breschi GL, Lagostena L, Russo G, Taverna S (2015) Selective activation of parvalbumin- or somatostatin-expressing interneurons triggers epileptic seizure like activity in mouse medial entorhinal cortex. J Neurophysiol 113(5):1616–1630. doi:10.1152/jn.00841.2014

    Article  CAS  PubMed  Google Scholar 

  15. Schiavone S, Sorce S, Dubois-Dauphin M, Jaquet V, Colaianna M, Zotti M, Cuomo V, Trabace L et al (2009) Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats. Biol Psychiatry 66(4):384–392. doi:10.1016/j.biopsych.2009.04.033

    Article  CAS  PubMed  Google Scholar 

  16. Matsumoto Y, Morinobu S, Yamamoto S, Matsumoto T, Takei S, Fujita Y, Yamawaki S (2013) Vorinostat ameliorates impaired fear extinction possibly via the hippocampal NMDA-CaMKII pathway in an animal model of posttraumatic stress disorder. Psychopharmacology (Berl) 229(1):51–62. doi:10.1007/s00213-013-3078-9

    Article  CAS  Google Scholar 

  17. Keller SM, Schreiber WB, Staib JM, Knox D (2015) Sex differences in the single prolonged stress model. Behav Brain Res 286:29–32. doi:10.1016/j.bbr.2015.02.034

    Article  PubMed  Google Scholar 

  18. Laukova M, Alaluf LG, Serova LI, Arango V, Sabban EL (2014) Early intervention with intranasal NPY prevents single prolonged stress-triggered impairments in hypothalamus and ventral hippocampus in male rats. Endocrinology 155(10):3920–3933. doi:10.1210/en.2014-1192

    Article  CAS  PubMed  Google Scholar 

  19. Hernandes MS, D'Avila JC, Trevelin SC, Reis PA, Kinjo ER, Lopes LR, Castro-Faria-Neto HC, Cunha FQ et al (2014) The role of Nox2-derived ROS in the development of cognitive impairment after sepsis. J Neuroinflammation 11:36. doi:10.1186/1742-2094-11-36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wu J, Dong L, Zhang M, Jia M, Zhang G, Qiu L, Ji M, Yang J (2013) Class I histone deacetylase inhibitor valproic acid reverses cognitive deficits in a mouse model of septic encephalopathy. Neurochem Res 38(11):2440–2449. doi:10.1007/s11064-013-1159-0

    Article  CAS  PubMed  Google Scholar 

  21. Ji M, Dong L, Jia M, Liu W, Zhang M, Ju L, Yang J, Xie Z et al (2014) Epigenetic enhancement of brain-derived neurotrophic factor signaling pathway improves cognitive impairments induced by isoflurane exposure in aged rats. Mol Neurobiol 50(3):937–944. doi:10.1007/s12035-014-8659-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ozdemir O, Selvi Y, Ozkol H, Tuluce Y, Besiroglu L, Aydin A (2012) Comparison of superoxide dismutase, glutathione peroxidase and adenosine deaminase activities between respiratory and nocturnal subtypes of patients with panic disorder. Neuropsychobiology 66(4):244–251. doi:10.1159/000341880

    Article  CAS  PubMed  Google Scholar 

  23. Yang JJ, Wang N, Yang C, Shi JY, Yu HY, Hashimoto K (2015) Serum interleukin-6 is a predictive biomarker for ketamine’s antidepressant effect in treatment-resistant patients with major depression. Biol Psychiatry 77(3):e19–e20. doi:10.1016/j.biopsych.2014.06.021

    Article  CAS  PubMed  Google Scholar 

  24. Miller MW, Sadeh N (2014) Traumatic stress, oxidative stress and post-traumatic stress disorder: neurodegeneration and the accelerated-aging hypothesis. Mol Psychiatry 19(11):1156–1162. doi:10.1038/mp.2014.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kann O, Papageorgiou IE, Draguhn A (2014) Highly energized inhibitory interneurons are a central element for information processing in cortical networks. J Cereb Blood Flow Metab 34:1270–1282. doi:10.1038/jcbfm.2014.104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Neske GT, Patrick SL, Connors BW (2015) Contributions of diverse excitatory and inhibitory neurons to recurrent network activity in cerebral cortex. J Neurosci 35(8):1089–1105. doi:10.1523/JNEUROSCI.2279-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brenhouse HC, Andersen SL (2011) Nonsteroidal anti-inflammatory treatment prevents delayed effects of early life stress in rats. Biol Psychiatry 70(5):434–440. doi:10.1016/j.biopsych.2011.05.006

    Article  CAS  PubMed  Google Scholar 

  28. Seo JS, Park JY, Choi J, Kim TK, Shin JH, Lee JK, Han PL (2012) NADPH oxidase mediates depressive behavior induced by chronic stress in mice. J Neurosci 32(28):9690–9699. doi:10.1523/JNEUROSCI.0794-12

    Article  CAS  PubMed  Google Scholar 

  29. Dugan LL, Ali SS, Shekhtman G, Roberts AJ, Lucero J, Quick KL, Behrens MM (2009) IL-6 mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase. PLoS One 4:e5518. doi:10.1371/journal.pone.0005518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Behrens MM, Ali SS, Dugan LL (2008) Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J Neurosci 28(51):13957–13966. doi:10.1523/JNEUROSCI.4457-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Keding TJ, Herringa RJ (2015) Abnormal structure of fear circuitry in pediatric post-traumatic stress disorder. Neuropsychopharmacology 40(3):537–545. doi:10.1038/npp.2014.239

    Article  PubMed  Google Scholar 

  32. Ji LL, Tong L, Xu BK, Fu CH, Shu W, Peng JB, Wang ZY (2014) Intra-hippocampal administration of ZIP alleviates depressive and anxiety-like responses in an animal model of posttraumatic stress disorder. Behav Brain Funct 10:28. doi:10.1186/1744-9081-10-28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No 81400876) and Science Foundation of Jinling Hospital (No 2015012).

Author information

Authors and Affiliations

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

    Fang-fang Liu, Xiao-ru Sun, Hui Zhang, Wei Pan, Xing-ming Wang, Jian-jun Yang & Mu-huo Ji

  2. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Lin-dong Yang

  3. Department of Anesthesiology, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China

    Hong-mei Yuan

Authors
  1. Fang-fang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin-dong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-ru Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xing-ming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian-jun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mu-huo Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hong-mei Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mu-huo Ji or Hong-mei Yuan.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Ethical Approval

The experimental protocol was approved by the Ethics Committee of Jinling Hospital, Nanjing University, and the study was conducted in accordance with the Guideline for the Care and Use of Laboratory Animals from the National Institutes of Health, USA.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Ff., Yang, Ld., Sun, Xr. et al. NOX2 Mediated-Parvalbumin Interneuron Loss Might Contribute to Anxiety-Like and Enhanced Fear Learning Behavior in a Rat Model of Post-Traumatic Stress Disorder. Mol Neurobiol 53, 6680–6689 (2016). https://doi.org/10.1007/s12035-015-9571-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-015-9571-x

Keywords

Search

Navigation