Molecular Neurobiology

, Volume 55, Issue 5, pp 3946–3958 | Cite as

rTMS Ameliorates PTSD Symptoms in Rats by Enhancing Glutamate Transmission and Synaptic Plasticity in the ACC via the PTEN/Akt Signalling Pathway

  • Gaohua Liu
  • Dayun Feng
  • Jian Wang
  • Haifeng Zhang
  • Zhengwu Peng
  • Min Cai
  • Jing Yang
  • Ruiguo Zhang
  • Huaning Wang
  • Shengxi Wu
  • Qingrong Tan


Repetitive transcranial magnetic stimulation (rTMS) is a novel physiological therapy that has been adopted to clinically treat psychiatric disorders. Our previous study indicated the potential therapeutic effect of rTMS on posttraumatic stress disorder (PTSD). However, the exact molecular mechanism is elusive. Currently, using the single prolonged stress (SPS) rat model for PTSD, we investigated the glutamatergic transmission and neural plasticity changes in the anterior cingulate cortex (ACC) after SPS induction and explored the protective effects and mechanism of rTMS treatment. We found that high-frequency rTMS (HrTMS, 15 Hz) treatment significantly relieved the impaired glutamatergic receptors in the ACC after SPS treatment by significantly increasing NMDAR and AMPAR expression. Simultaneously, HrTMS blocked inhibited neuronal phosphatase and tensin homologue on chromosome 10 (PTEN)/Akt signalling in the ACC after SPS treatment by decreasing PTEN expression and increasing Akt phosphorylation, which is critically involved in the regulation of memory and synaptic plasticity. The PTEN inhibitors bpV and small interfering RNA and the Akt inhibitor wortmannin were stereotaxically administered to the ACC after SPS treatment to advance the mechanistic study. Analysis by Western blot, double immunofluorescence, Golgi staining and behavioural tests demonstrated that the effects of rTMS on PTEN/Akt activation, glutamatergic receptor expression, neuronal synaptic plasticity and PTSD-related behaviours induced by SPS treatment were enhanced by PTEN inhibition and blocked by Akt inhibition in the ACC. Our study provides convincing evidence for the effectiveness of rTMS treatment on PTSD and suggests that its potential mechanism involves remodelling neuronal synaptic plasticity via the PTEN/Akt signalling pathway.


PTSD rTMS ACC PTEN Akt Glutamate receptor 


Author Contributions

Tan QR and Wu SX designed the study and wrote the protocols. Liu GH, Feng DY and Wang J completed the animal experiments and the statistical analysis. Cai M and Peng ZW participated in the behavioural tests. Zhang RG and Zhang HF participated in the morphology experiments. Yang J participated in the Western blot analysis. Wang HN managed the literature edition. All authors read and approved the final manuscript.

Compliance with Ethical Standards

Funding Sources

This work was supported by the State Key Program of the National Natural Science Foundation of China [grant number 81630032] and the National Natural Science Foundation of China [grant numbers 81371240 and 81571309].

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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  1. 1.
    Stein DJ, Seedat S, Iversen A, Wessely S (2007) Post-traumatic stress disorder: medicine and politics. Lancet 369:139–144CrossRefPubMedGoogle Scholar
  2. 2.
    Jackson G (1991) The rise of post-traumatic stress disorders. BMJ 303:533–534CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Steenkamp MM, Litz BT (2014) Prolonged exposure therapy in veterans affairs: the full picture. JAMA Psychiatry 71:211CrossRefPubMedGoogle Scholar
  4. 4.
    Fonagy P (2015) The effectiveness of psychodynamic psychotherapies: an update. World Psychiatry 14:137–150CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Brady K, Pearlstein T, Asnis GM, Baker D, Rothbaum B, Sikes CR, Farfel GM (2000) Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA 283:1837–1844CrossRefPubMedGoogle Scholar
  6. 6.
    Tarrier N, Pilgrim H, Sommerfield C, Faragher B, Reynolds M, Graham E, Barrowclough C (1999) A randomized trial of cognitive therapy and imaginal exposure in the treatment of chronic posttraumatic stress disorder. J Consult Clin Psychol 67:13–18CrossRefPubMedGoogle Scholar
  7. 7.
    Rossi S, Hallett M, Rossini PM, Pascual-Leone A (2009) Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 120:2008–2039CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Aleman A, Sommer IE, Kahn RS (2007) Efficacy of slow repetitive transcranial magnetic stimulation in the treatment of resistant auditory hallucinations in schizophrenia: a meta-analysis. J Clin Psychiatry 68:416–421CrossRefPubMedGoogle Scholar
  9. 9.
    Cohen H, Kaplan Z, Kotler M, Kouperman I, Moisa R, Grisaru N (2004) Repetitive transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in posttraumatic stress disorder: a double-blind, placebo-controlled study. Am J Psychiatry 161:515–524CrossRefPubMedGoogle Scholar
  10. 10.
    Woodward SH, Kaloupek DG, Streeter CC, Martinez C, Schaer M, Eliez S (2006) Decreased anterior cingulate volume in combat-related PTSD. Biol Psychiatry 59:582–587CrossRefPubMedGoogle Scholar
  11. 11.
    Schulz-Heik RJ, Schaer M, Eliez S, Hallmayer JF, Lin X, Kaloupek DG, Woodward SH (2011) Catechol-O-methyltransferase Val158Met polymorphism moderates anterior cingulate volume in posttraumatic stress disorder. Biol Psychiatry 70:1091–1096CrossRefPubMedGoogle Scholar
  12. 12.
    Sekiguchi A, Sugiura M, Taki Y, Kotozaki Y, Nouchi R, Takeuchi H, Araki T, Hanawa S et al (2013) Brain structural changes as vulnerability factors and acquired signs of post-earthquake stress. Mol Psychiatry 18:618–623CrossRefPubMedGoogle Scholar
  13. 13.
    Thomaes K, Dorrepaal E, Draijer N, Jansma EP, Veltman DJ, van Balkom AJ (2014) Can pharmacological and psychological treatment change brain structure and function in PTSD? A systematic review. J Psychiatr Res 50:1–15CrossRefPubMedGoogle Scholar
  14. 14.
    Fani N, Ashraf A, Afzal N, Jawed F, Kitayama N, Reed L, Bremner JD (2011) Increased neural response to trauma scripts in posttraumatic stress disorder following paroxetine treatment: a pilot study. Neurosci Lett 491:196–201CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Citri A, Malenka RC (2008) Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology 33:18–41CrossRefPubMedGoogle Scholar
  16. 16.
    Knox D, Perrine SA, George SA, Galloway MP, Liberzon I (2010) Single prolonged stress decreases glutamate, glutamine, and creatine concentrations in the rat medial prefrontal cortex. Neurosci Lett 480:16–20CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Downward J (1998) Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 10:262–267CrossRefPubMedGoogle Scholar
  18. 18.
    Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927CrossRefPubMedGoogle Scholar
  19. 19.
    Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SG (2000) Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nat Neurosci 3:661–669CrossRefPubMedGoogle Scholar
  20. 20.
    Chen BS, Roche KW (2009) Growth factor-dependent trafficking of cerebellar NMDA receptors via protein kinase B/Akt phosphorylation of NR2C. Neuron 62:471–478CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, Li Y, Baker SJ et al (2006) Pten regulates neuronal arborization and social interaction in mice. Neuron 50:377–388CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sanna PP, Cammalleri M, Berton F, Simpson C, Lutjens R, Bloom FE, Francesconi W (2002) Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region. J Neurosci 22:3359–3365PubMedGoogle Scholar
  23. 23.
    Jurado S, Benoist M, Lario A, Knafo S, Petrok CN, Esteban JA (2010) PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression. EMBO J 29:2827–2840CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Chen C, Ji M, Xu Q, Zhang Y, Sun Q, Liu J, Zhu S, Li W (2015) Sevoflurane attenuates stress-enhanced fear learning by regulating hippocampal BDNF expression and Akt/GSK-3beta signaling pathway in a rat model of post-traumatic stress disorder. J Anesth 29:600–608CrossRefPubMedGoogle Scholar
  25. 25.
    Liberzon I, Krstov M, Young EA (1997) Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology 22:443–453CrossRefPubMedGoogle Scholar
  26. 26.
    Khan S, Liberzon I (2004) Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD. Psychopharmacology 172:225–229CrossRefPubMedGoogle Scholar
  27. 27.
    Takahashi T, Morinobu S, Iwamoto Y, Yamawaki S (2006) Effect of paroxetine on enhanced contextual fear induced by single prolonged stress in rats. Psychopharmacology 189:165–173CrossRefPubMedGoogle Scholar
  28. 28.
    Imanaka A, Morinobu S, Toki S, Yamawaki S (2006) Importance of early environment in the development of post-traumatic stress disorder-like behaviors. Behav Brain Res 173:129–137CrossRefPubMedGoogle Scholar
  29. 29.
    Schweimer J, Hauber W (2005) Involvement of the rat anterior cingulate cortex in control of instrumental responses guided by reward expectancy. Learn Mem 12:334–342CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Overstreet DH, Commissaris RC, De La Garza RN, File SE, Knapp DJ, Seiden LS (2003) Involvement of 5-HT1A receptors in animal tests of anxiety and depression: evidence from genetic models. Stress 6:101–110CrossRefPubMedGoogle Scholar
  31. 31.
    Feng D, Guo B, Liu G, Wang B, Wang W, Gao G, Qin H, Wu S (2015) FGF2 alleviates PTSD symptoms in rats by restoring GLAST function in astrocytes via the JAK/STAT pathway. Eur Neuropsychopharmacol 25:1287–1299CrossRefPubMedGoogle Scholar
  32. 32.
    Wang HN, Bai YH, Chen YC, Zhang RG, Wang HH, Zhang YH, Gan JL, Peng ZW et al (2015) Repetitive transcranial magnetic stimulation ameliorates anxiety-like behavior and impaired sensorimotor gating in a rat model of post-traumatic stress disorder. PLoS One 10:e0117189CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Zehle S, Bock J, Jezierski G, Gruss M, Braun K (2007) Methylphenidate treatment recovers stress-induced elevated dendritic spine densities in the rodent dorsal anterior cingulate cortex. Dev Neurobiol 67:1891–1900CrossRefPubMedGoogle Scholar
  34. 34.
    Chen, R., Spencer, D. C., Weston, J., & Nolan, S. J. (2016) Transcranial magnetic stimulation for the treatment of epilepsy. Cochrane Database Syst Rev, CD011025Google Scholar
  35. 35.
    Ongur D, Ferry AT, Price JL (2003) Architectonic subdivision of the human orbital and medial prefrontal cortex. J Comp Neurol 460:425–449CrossRefPubMedGoogle Scholar
  36. 36.
    Ongur D, Price JL (2000) The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex 10:206–219CrossRefPubMedGoogle Scholar
  37. 37.
    Butter CM, Snyder DR (1972) Alterations in aversive and aggressive behaviors following orbital frontal lesions in rhesus monkeys. Acta Neurobiol Exp (Wars) 32:525–565Google Scholar
  38. 38.
    Bremner JD, Mletzko T, Welter S, Quinn S, Williams C, Brummer M, Siddiq S, Reed L et al (2005) Effects of phenytoin on memory, cognition and brain structure in post-traumatic stress disorder: a pilot study. J Psychopharmacol 19:159–165CrossRefPubMedGoogle Scholar
  39. 39.
    Kitayama N, Quinn S, Bremner JD (2006) Smaller volume of anterior cingulate cortex in abuse-related posttraumatic stress disorder. J Affect Disord 90:171–174CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Kasai K, Yamasue H, Gilbertson MW, Shenton ME, Rauch SL, Pitman RK (2008) Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biol Psychiatry 63:550–556CrossRefPubMedGoogle Scholar
  41. 41.
    Kim MJ, Chey J, Chung A, Bae S, Khang H, Ham B, Yoon SJ, Jeong DU et al (2008) Diminished rostral anterior cingulate activity in response to threat-related events in posttraumatic stress disorder. J Psychiatr Res 42:268–277CrossRefPubMedGoogle Scholar
  42. 42.
    Offringa R, Handwerger BK, Staples LK, Dubois SJ, Hughes KC, Pfaff DL, Vanelzakker MB, Davis FC et al (2013) Diminished rostral anterior cingulate cortex activation during trauma-unrelated emotional interference in PTSD. Biol Mood Anxiety Disord 3:10CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kelmendi B, Adams TG, Yarnell S, Southwick S, Abdallah CG, Krystal JH (2016) PTSD: from neurobiology to pharmacological treatments. Eur J Psychotraumatol 7:31858CrossRefPubMedGoogle Scholar
  44. 44.
    Yang ZY, Quan H, Peng ZL, Zhong Y, Tan ZJ, Gong QY (2015) Proton magnetic resonance spectroscopy revealed differences in the glutamate + glutamine/creatine ratio of the anterior cingulate cortex between healthy and pediatric post-traumatic stress disorder patients diagnosed after 2008 Wenchuan earthquake. Psychiatry Clin Neurosci 69:782–790CrossRefPubMedGoogle Scholar
  45. 45.
    Beaulieu JM (2012) A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health. J Psychiatry Neurosci 37:7–16CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Shehata M, Matsumura H, Okubo-Suzuki R, Ohkawa N, Inokuchi K (2012) Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. J Neurosci 32:10413–10422CrossRefPubMedGoogle Scholar
  47. 47.
    Trotter J, Lee GH, Kazdoba TM, Crowell B, Domogauer J, Mahoney HM, Franco SJ, Muller U et al (2013) Dab1 is required for synaptic plasticity and associative learning. J Neurosci 33:15652–15668CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Garcia-Junco-Clemente P, Golshani P (2014) PTEN: a master regulator of neuronal structure, function, and plasticity. Commun Integr Biol 7:e28358CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Grillon C, Southwick SM, Charney DS (1996) The psychobiological basis of posttraumatic stress disorder. Mol Psychiatry 1:278–297PubMedGoogle Scholar
  50. 50.
    Hopper JW, Frewen PA, van der Kolk BA, Lanius RA (2007) Neural correlates of reexperiencing, avoidance, and dissociation in PTSD: symptom dimensions and emotion dysregulation in responses to script-driven trauma imagery. J Trauma Stress 20:713–725CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Psychiatry, Xijing HospitalFourth Military Medical UniversityXi’anPeople’s Republic of China
  2. 2.Department of Neurobiology and Institute of NeuroscienceFourth Military Medical UniversityXi’anPeople’s Republic of China
  3. 3.Department of Cardiac SurgeryGeneral Hospital of Chengdu Military RegionChengduPeople’s Republic of China

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