Advertisement

Stathmin Regulates Spatiotemporal Variation in the Memory Loop in Single-Prolonged Stress Rats

  • 20 Accesses

Abstract

Posttraumatic stress disorder (PTSD) is closely related to brain structures of the memory loop such as the hippocampus, amygdala, and medial prefrontal cortex (mPFC). The fear gene stathmin plays an important role in regulating fear memory. However, whether the fear gene stathmin is related to fear memory loop anomalies caused by PTSD is unclear. A single-prolonged stress (SPS) rat model of PTSD was constructed. Wistar rats were randomly divided into 5 groups: the control group, SPS 1-day group, SPS 4-day group, SPS 7-day group, and SPS 14-day group. Then, we measured the protein and mRNA expression of stathmin, p-stathmin (Ser16, Ser25, Ser38, and Ser63), β-tubulin, and MAP-1B in the hippocampus, amygdala, and mPFC in the 5 groups by immunohistochemistry, Western blotting, and qRT-PCR. The expression of the stathmin protein in the hippocampus, mPFC, and amygdala of the rat memory loop decreased gradually in the SPS 1-day group, the SPS 4-day group, and the SPS 7-day group, in which it was the lowest, and then increased. The trend of the expression of stathmin mRNA in the three areas of the memory loop was consistent with the trend of the expression of the stathmin protein. The trend of the protein expression of p-stathmin (Ser25 and Ser38) was opposite of that of stathmin; it reached a peak on the 7th day, and then decreased in the hippocampus. The protein expression of p-stathmin (Ser63) showed the same trend in the mPFC. The protein and mRNA expression of β-tubulin and MAP-1B was consistent with that of p-stathmin; it reached a peak on the 7th day, and then decreased in the rat hippocampus, mPFC, and amygdala. Stathmin in the memory loop, especially in the hippocampus, regulates microtubule structure through its phosphorylation at Ser25 and Ser38 and thereby participates in the mediation of fear memory abnormalities in PTSD.

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

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

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

References

  1. Adhikari S, Bhatia M (2008) H2S-induced pancreatic acinar cell apoptosis is mediated via JNK and p38 MAP kinase. J Cell Mol Med 12(4):1374–1383. https://doi.org/10.1111/j.1582-4934.2008.00318.x

  2. Alesi GN, Jin L, Li D, Magliocca KR, Kang Y, Chen ZG, Shin DM, Khuri FR, Kang S (2016) RSK2 signals through stathmin to promote microtubule dynamics and tumor metastasis. Oncogene 35(41):5412–5421. https://doi.org/10.1038/onc.2016.79

  3. Bailey ME, Sackett DL, Ross JL (2015) Katanin severing and binding microtubules are inhibited by tubulin carboxy tails. Biophys J 109(12):2546–2561. https://doi.org/10.1016/j.bpj.2015.11.011

  4. Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM et al (1995) MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry 152(7):973–981. https://doi.org/10.1176/ajp.152.7.973

  5. Bremner JD, Randall P, Vermetten E, Staib L, Bronen RA, Mazure C et al (1997) Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse—a preliminary report. Biol Psychiatry 41(1):23–32

  6. Caunt CJ, Armstrong SP, Rivers CA, Norman MR, McArdle CA (2008) Spatiotemporal regulation of ERK2 by dual specificity phosphatases. J Biol Chem 283(39):26612–26623. https://doi.org/10.1074/jbc.m801500200

  7. Cheon MS, Fountoulakis M, Cairns NJ, Dierssen M, Herkner K, Lubec G (2001) Decreased protein levels of stathmin in adult brains with down syndrome and Alzheimer’s disease. J Neural Transm Suppl 61:281–288

  8. Drerup CM, Lusk S, Nechiporuk A (2016) Kif1B interacts with KBP to promote axon elongation by localizing a microtubule regulator to growth cones. J Neurosci 36(26):7014–7026. https://doi.org/10.1523/JNEUROSCI.0054-16.2016

  9. Epelboin Y, Quintric L, Guévélou E, Boudry P, Pichereau V, Corporeau C (2016) The Kinome of Pacific Oyster Crassostrea gigas, its expression during development and in response to environmental factors. PLoS One 11(5):e0155435. https://doi.org/10.1371/journal.pone.0155435

  10. Feng T, Xu J, He P, Chen Y, Fang R, Shao X (2017) Decrease in stathmin expression by arsenic trioxide inhibits the proliferation and invasion of osteosarcoma cells via the MAPK signal pathway. Oncol Lett 14(2):1333–1340. https://doi.org/10.3892/ol.2017.6347

  11. Gilpin NW, Weiner JL (2016) Neurobiology of comorbid post-traumatic stress disorder and alcohol-use disorder. Genes Brain Behav 16(1):15–43. https://doi.org/10.1111/gbb.12349

  12. Gradin HM, Larsson N, Marklund U, Gullberg M (1998) Regulation of microtubule dynamics by extracellular signals: cAMP-dependent protein kinase switches off the activity of oncoprotein 18 in intact cells. J Cell Biol 140(1):131–141

  13. Gurvits TV, Shenton ME, Hokama H, Ohta H, Lasko NB, Gilbertson MW, Pitman RK (1996) Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry 40(11):1091–1099. https://doi.org/10.1016/S0006-3223(96)00229-6

  14. Han F, Yan S, Shi Y (2013) Single-prolonged stress induces endoplasmic reticulum-dependent apoptosis in the hippocampus in a rat model of post-traumatic stress disorder. PLoS One 8(7):e69340. https://doi.org/10.1371/journal.pone.0069340

  15. Han F, Ding J, Shi Y (2014) Expression of amygdala mineralocorticoid receptor and glucocorticoid receptor in the single-prolonged stress rats. BMC Neurosci 15:77. https://doi.org/10.1186/1471-2202-15-77

  16. Han F, Jiang J, Ding J, Liu H, Xiao B, Shi Y (2017) Change of Rin1 and stathmin in the animal model of traumatic stresses. Front Behav Neurosci 11:62. https://doi.org/10.3389/fnbeh.2017.00062

  17. Hirokawa N, Takemura R (2005) Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 6(3):201–214. https://doi.org/10.1038/nrn1624

  18. Jin LW, Masliah E, Iimoto D, Deteresa R, Mallory M, Sundsmo M, Mori N, Sobel A, Saitoh T (1996) Neurofibrillary tangle-associated alteration of stathmin in Alzheimer’s disease. Neurobiol Aging 17(3):331–341. https://doi.org/10.1016/0197-4580(96)00021-8

  19. Küntziger T, Gavet O, Manceau V, Sobel A, Bornens M (2001) Stathmin/Op18 phosphorylation is regulated by microtubule assembly. Mol Biol Cell 12(2):437–448. https://doi.org/10.1091/mbc.12.2.437

  20. Leuner B, Sabihi S (2016) The birth of new neurons in the maternal brain: hormonal regulation and functional implications. Front Neuroendocrinol 41:99–113. https://doi.org/10.1016/j.yfrne.2016.02.004

  21. Li XM, Han F, Liu DJ, Shi YX (2010) Single-prolonged stress induced mitochondrial-dependent apoptosis in hippocampus in the rat model of post-traumatic stress disorder. J Chem Neuroanat 40(3):248–255. https://doi.org/10.1016/j.jchemneu.2010.07.001

  22. Li Y, Han F, Shi Y (2015) Changes in integrin αv, vinculin and connexin43 in the medial prefrontal cortex in rats under single-prolonged stress. Mol Med Rep 11(4):2520–2526. https://doi.org/10.3892/mmr.2014.3030

  23. Li L, Lei D, Li L, Huang X, Suo X, Xiao F, Kuang W, Li J, Bi F, Lui S, Kemp GJ, Sweeney JA, Gong Q (2016) White matter abnormalities in post-traumatic stress disorder following a specific traumatic event. EBioMedicine 4:176–183. https://doi.org/10.1016/j.ebiom.2016.01.012

  24. Lisieski MJ, Eagle AL, Conti AC, Liberzon I, Perrine SA (2018) Single-prolonged stress: a review of two decades of progress in a rodent model of post-traumatic stress disorder. Front Psych 9:196. https://doi.org/10.3389/fpsyt.2018.00196

  25. Magron A, Elowe S, Carreau M (2015) The Fanconi anemia C protein binds to and regulates stathmin-1 phosphorylation. PLoS One 10(10):e0140612. https://doi.org/10.1371/journal.pone.0140612

  26. Manka SW, Moores CA (2018) Microtubule structure by cryo-EM: snapshots of dynamic instability. Essays Biochem 62(6):737–751. https://doi.org/10.1042/EBC20180031

  27. Marklund U, Larsson N, Gradin HM, Brattsand G, Gullberg M (1996) Oncoprotein 18 is a phosphorylation-responsive regulator of microtubule dynamics. EMBO J 15(19):5290–5298

  28. Melander Gradin H, Marklund U, Larsson N, Chatila TA, Gullberg M (1997) Regulation of microtubule dynamics by Ca2+/calmodulin-dependent kinase IV/Gr-dependent phosphorylation of oncoprotein 18. Mol Cell Biol 17(6):3459–3467

  29. Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW, Liberzon I (2012) Biological studies of post-traumatic stress disorder. Nature reviews. Neuroscience 13(11):769–787. https://doi.org/10.1038/nrn3339

  30. Ramkumar A, Jong BY, Ori-McKenney KM (2017) ReMAPping the microtubule landscape: how phosphorylation dictates the activities of microtubule-associated proteins. Dev Dyn 247(1):138–155. https://doi.org/10.1002/dvdy.24599

  31. Ringhoff DN, Cassimeris L (2009) Gene expression profiles in mouse embryo fibroblasts lacking stathmin, a microtubule regulatory protein, reveal changes in the expression of genes contributing to cell motility. BMC Genomics 10:343. https://doi.org/10.1186/1471-2164-10-343

  32. Shumyatsky GP, Tsvetkov E, Malleret G, Vronskaya S, Hatton M, Hampton L, Battey JF, Dulac C, Kandel ER, Bolshakov VY (2002) Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 111:905–918. https://doi.org/10.1016/s0092-8674(02)01116-9

  33. Shvil E, Rusch HL, Sullivan GM, Neria Y (2013) Neural, psychophysiological, and behavioral markers of fear processing in PTSD: a review of the literature. Curr Psychiatry Rep 15(5):358. https://doi.org/10.1007/s11920-013-0358-3

  34. Siehl S, King JA, Burgess N, Flor H, Nees F (2018) Structural white matter changes in adults and children with posttraumatic stress disorder: a systematic review and meta-analysis. NeuroImage Clin 19:581–598. https://doi.org/10.1016/j.nicl.2018.05.013

  35. Silva VC, Cassimeris L (2013) Stathmin and microtubules regulate mitotic entry in HeLa cells by controlling activation of both Aurora kinase A and Plk1. Mol Biol Cell 24(24):3819–3831. https://doi.org/10.1091/mbc.E13-02-0108

  36. Stanley IH, Boffa JW, Tran JK, Schmidt NB, Joiner TE, Vujanovic AA (2019) Posttraumatic stress disorder symptoms and mindfulness facets in relation to suicide risk among firefighters. J Clin Psychol 75(4):696–709. https://doi.org/10.1002/jclp.22748

  37. Steinmetz MO, Jahnke W, Towbin H, García-Echeverría C, Voshol H, Müller D, van Oostrum J (2001) Phosphorylation disrupts the central helix in Op18/stathmin and suppresses binding to tubulin. EMBO Rep 2(6):505–510. https://doi.org/10.1093/embo-reports/kve105

  38. Uchida S, Martel G, Pavlowsky A, Takizawa S, Hevi C, Watanabe Y, Kandel ER, Alarcon JM, Shumyatsky GP (2014) Learning-induced and stathmin-dependent changes in microtubule stability are critical for memory and disrupted in ageing. Nat Commun 5:4389. https://doi.org/10.1038/ncomms5389

  39. Weiss T, Skelton K, Phifer J, Jovanovic T, Gillespie CF, Smith A, Umpierrez G, Bradley B, Ressler KJ (2011) Posttraumatic stress disorder is a risk factor for metabolic syndrome in an impoverished urban population. Gen Hosp Psychiatry 33(2):135–142. https://doi.org/10.1016/j.genhosppsych.2011.01.002

  40. Xu K, Harrison RE (2015) Down-regulation of stathmin is required for the phenotypic changes and classical activation of macrophages. J Biol Chem 290(31):19245–19260. https://doi.org/10.1074/jbc.M115.639625

  41. Yadav P, Selvaraj BT, Bender FL, Behringer M, Moradi M, Sivadasan R, Sendtner M (2016) Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling. Acta Neuropathol 132(1):93–110. https://doi.org/10.1007/s00401-016-1564-y

  42. Yu B, Wen L, Xiao B, Han F, Shi Y (2014) Single prolonged stress induces ATF6 alpha-dependent endoplasmic reticulum stress and the apoptotic process in medial frontal cortex neurons. BMC Neurosci 15:115. https://doi.org/10.1186/s12868-014-0115-5

  43. Zhao E, Amir M, Lin Y, Czaja MJ (2014) Stathmin mediates hepatocyte resistance to death from oxidative stress by down regulating JNK. PLoS One 9(10):e109750. https://doi.org/10.1371/journal.pone.0109750

Download references

Acknowledgments

The authors are grateful to all staff members of the China Medical University Experiment Center for their technical support.

Funding Information

This work was supported by grants from the China National Natural Science Foundation (81571324) and the Science and Technology Project of Liao Ning Province, China (2017225011).

Author information

Correspondence to Yanhao Xu or Yuxiu Shi.

Ethics declarations

The animal experiments were performed according to protocols approved by the Ethical Committee of Animal Research at the China Medical University, and all efforts were made to minimize the number of animals used and their suffering.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shan, W., Han, F., Xu, Y. et al. Stathmin Regulates Spatiotemporal Variation in the Memory Loop in Single-Prolonged Stress Rats. J Mol Neurosci (2020). https://doi.org/10.1007/s12031-019-01459-w

Download citation

Keywords

  • Single-prolonged stress
  • Stathmin
  • P-stathmin
  • Memory loop
  • Spatiotemporal variation