Molecular Neurobiology

, Volume 53, Issue 2, pp 1247–1253 | Cite as

Inhibition of Rac1 Activity in the Hippocampus Impairs the Forgetting of Contextual Fear Memory

  • Lizhu Jiang
  • Rongrong Mao
  • Qixin Zhou
  • Yuexiong Yang
  • Jun Cao
  • Yuqiang Ding
  • Yuan Yang
  • Xia Zhang
  • Lingjiang Li
  • Lin Xu


Fear is crucial for survival, whereas hypermnesia of fear can be detrimental. Inhibition of the Rac GTPase is recently reported to impair the forgetting of initially acquired memory in Drosophila. Here, we investigated whether inhibition of Rac1 activity in rat hippocampus could contribute to the hypermnesia of contextual fear. We found that spaced but not massed training of contextual fear conditioning caused inhibition of Rac1 activity in the hippocampus and heightened contextual fear. Furthermore, intrahippocampal injection of the Rac1 inhibitor NSC23766 heightened contextual fear in massed training, while Rac1 activator CN04-A weakened contextual fear in spaced training rats. Our study firstly demonstrates that contextual fear memory in rats is actively regulated by Rac1 activity in the hippocampus, which suggests that the forgetting impairment of traumatic events in posttraumatic stress disorder may be contributed to the pathological inhibition of Rac1 activity in the hippocampus.


GTPase Rac1 Hypermnesia Hippocampus Forgetting Contextual fear memory 



Posttraumatic stress disorder



We thank LP Wang for technical assistance and Lab members for their critical comments. This work was supported by the National Basic Research Program of China (2013CB835103 and 2009CB918303), Strategic Priority Research Program of the Chinese Academy of Science (XDB02020002), NSFC-CIHR Joint Grant (81161120536), National Natural Science Foundation of China (31100786, 30860089, 930830046, 81171286, 91232714, 81460216, U1032605, and U1132602), and Science and Technology Program of Yunnan Province (2013GA003 and 2013FA048). There are no competing financial interests in relation to the work.

Supplementary material

12035_2015_9093_MOESM1_ESM.doc (68 kb)
ESM 1 (DOC 67 kb)
12035_2015_9093_MOESM2_ESM.tif (4.4 mb)
ESM 2 (TIFF 4540 kb)
12035_2015_9093_MOESM3_ESM.tif (1.8 mb)
ESM 3 (TIFF 1816 kb)
12035_2015_9093_MOESM4_ESM.tif (478 kb)
ESM 4 (TIFF 478 kb)


  1. 1.
    Johansen JP, Cain CK, Ostroff LE, LeDoux JE (2011) Molecular mechanisms of fear learning and memory. Cell 147(3):509–524PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Yehuda R, LeDoux J (2007) Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56(1):19–32CrossRefPubMedGoogle Scholar
  3. 3.
    Eichenbaum H (2000) A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 1(1):41–50CrossRefPubMedGoogle Scholar
  4. 4.
    Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106(2):274–285CrossRefPubMedGoogle Scholar
  5. 5.
    Grillon C, Southwick SM, Charney DS (1996) The psychobiological basis of posttraumatic stress disorder. Mol Psychiatry 1(4):278–297PubMedGoogle Scholar
  6. 6.
    Mahan AL, Ressler KJ (2012) Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci 35(1):24–35PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Wixted JT (2004) The psychology and neuroscience of forgetting. Annu Rev Psychol 55:235–269CrossRefPubMedGoogle Scholar
  8. 8.
    Shuai Y, Lu B, Hu Y, Wang L, Sun K, Zhong Y (2010) Forgetting is regulated through Rac activity in Drosophila. Cell 140(4):579–589CrossRefPubMedGoogle Scholar
  9. 9.
    O'Kane EM, Stone TW, Morris BJ (2003) Distribution of Rho family GTPases in the adult rat hippocampus and cerebellum. Brain Res Mol Brain Res 114(1):1–8CrossRefPubMedGoogle Scholar
  10. 10.
    Olenik C, Barth H, Just I, Aktories K, Meyer DK (1997) Gene expression of the small GTP-binding proteins RhoA, RhoB, Rac1, and Cdc42 in adult rat brain. Brain Res Mol Brain Res 52(2):263–269CrossRefPubMedGoogle Scholar
  11. 11.
    Haditsch U, Leone DP, Farinelli M, Chrostek-Grashoff A, Brakebusch C, Mansuy IM et al (2009) A central role for the small GTPase Rac1 in hippocampal plasticity and spatial learning and memory. Mol Cell Neurosci 41(4):409–419PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Martinez LA, Tejada-Simon MV (2011) Pharmacological inactivation of the small GTPase Rac1 impairs long-term plasticity in the mouse hippocampus. Neuropharmacology 61(1–2):305–312PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Kim JJ, Fanselow MS (1992) Modality-specific retrograde amnesia of fear. Science 256(5057):675–677CrossRefPubMedGoogle Scholar
  14. 14.
    Naqib F, Sossin WS, Farah CA (2012) Molecular determinants of the spacing effect. Neural Plast 2012:581291PubMedCentralPubMedGoogle Scholar
  15. 15.
    Ebbinghaus H (1913) Memory: A contribution to experimental psychology (H. A. Ruger & C. E. Bussenius, Trans.). N Y Columbia Univ Teach Coll 39(2):358–358Google Scholar
  16. 16.
    Bai H-Y, Cao J, Liu N, Xu L, Luo J-H (2009) Sexual behavior modulates contextual fear memory through dopamine D1/D5 receptors. Hippocampus 19(3):289–298CrossRefPubMedGoogle Scholar
  17. 17.
    Randolf Menzel GM, Menzel R, Greggers U (2001) Massed and spaced learning in honeybees: the role of CS, US, the intertrial interval, and the test interval. Learn Mem 8:198–208PubMedCentralCrossRefGoogle Scholar
  18. 18.
    Robert C, Barnet NJG, Miller RR (1995) Trial spacing effects in Pavlovian conditioning: a role for local context. Anim Learn Behav 23(3):340–348CrossRefGoogle Scholar
  19. 19.
    Blanchard DC, Blanchard RJ (1972) Innate and conditioned reactions to threat in rats with amygdaloid lesions. J Comp Physiol Psychol 81(2):281–290CrossRefPubMedGoogle Scholar
  20. 20.
    Li Z, Zhou Q, Li L, Mao R, Wang M, Peng W et al (2005) Effects of unconditioned and conditioned aversive stimuli in an intense fear conditioning paradigm on synaptic plasticity in the hippocampal CA1 area in vivo. Hippocampus 15(6):815–824CrossRefPubMedGoogle Scholar
  21. 21.
    Mark E, Bouton RCB (1980) Conditioned fear assessed by freezing and by the suppression of three different baselines. Anim Learn Behav 8(3):429–434CrossRefGoogle Scholar
  22. 22.
    Castillo-Lluva S, Tatham MH, Jones RC, Jaffray EG, Edmondson RD, Hay RT et al (2010) SUMOylation of the GTPase Rac1 is required for optimal cell migration. Nat Cell Biol 12(11):1078–1085PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Chen LY, Rex CS, Babayan AH, Kramar EA, Lynch G, Gall CM et al (2010) Physiological activation of synaptic Rac>PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome. J Neurosci Off J Soc Neurosci 30(33):10977–10984CrossRefGoogle Scholar
  24. 24.
    Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y (2004) Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A 101(20):7618–7623PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    APA (1994) American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Press, WashingtonGoogle Scholar
  26. 26.
    Pagani MR, Oishi K, Gelb BD, Zhong Y (2009) The phosphatase SHP2 regulates the spacing effect for long-term memory induction. Cell 139(1):186–198PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    McEwen BS (2000) The neurobiology of stress: from serendipity to clinical relevance. Brain Res 886(1–2):172–189CrossRefPubMedGoogle Scholar
  28. 28.
    Christoffel DJ, Golden SA, Russo SJ (2011) Structural and synaptic plasticity in stress-related disorders. Rev Neurosci 22(5):535–549PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K et al (2013) Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med 19(3):337–344PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Gilbertson MW, Shenton ME, Ciszewski A, Kasai K, Lasko NB, Orr SP et al (2002) Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci 5(11):1242–1247PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Dudai Y (2002) Molecular bases of long-term memories: a question of persistence. Curr Opin Neurobiol 12(2):211–216CrossRefPubMedGoogle Scholar
  32. 32.
    Lamprecht R, LeDoux J (2004) Structural plasticity and memory. Nat Rev Neurosci 5(1):45–54CrossRefPubMedGoogle Scholar
  33. 33.
    Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361(6407):31–39CrossRefPubMedGoogle Scholar
  34. 34.
    Xu L, Anwyl R, Rowan MJ (1998) Spatial exploration induces a persistent reversal of long-term potentiation in rat hippocampus. Nature 394(6696):891–894CrossRefPubMedGoogle Scholar
  35. 35.
    Jovanovic T, Ressler KJ (2010) How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. Am J Psychiatry 167(6):648–662PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Lizhu Jiang
    • 1
    • 6
  • Rongrong Mao
    • 2
  • Qixin Zhou
    • 2
  • Yuexiong Yang
    • 2
  • Jun Cao
    • 2
  • Yuqiang Ding
    • 3
  • Yuan Yang
    • 4
  • Xia Zhang
    • 5
  • Lingjiang Li
    • 1
  • Lin Xu
    • 2
  1. 1.Mental Health Institute, The 2nd Xiangya Hospital, Key Lab of Psychiatry and Mental Health of Hunan ProvinceCentral South UniversityChangshaChina
  2. 2.Key Lab of Animal Models and Human Disease Mechanisms, Kunming Institute of ZoologyThe Chinese Academy of SciencesKunmingChina
  3. 3.Key Laboratory of Arrhythmias, Ministry of Education, East HospitalTongji University School of MedicineShanghaiChina
  4. 4.Department of PhysiologyKunming Medical UniversityKunmingChina
  5. 5.Institute of Mental Health Research and Departments of Psychiatry and Cellular & Molecular MedicineUniversity of OttawaOttawaCanada
  6. 6.Neurology, Kunming Affiliated Hospital of Dali UniversityKunmingChina

Personalised recommendations