Journal of Neuro-Oncology

, Volume 103, Issue 3, pp 469–477 | Cite as

Impaired hippocampal synaptic plasticity in C6 glioma-bearing rats

  • Yi-yi Wang
  • Shi-chang Liu
  • Zhuo YangEmail author
  • Tao ZhangEmail author
Laboratory Investigation - Human/Animal Tissue


For many glioblastoma multiforme patients, cognitive deficits are part of the disease process. In this study we attempted to determine the role of synaptic plasticity and glutamate (Glu) in C6 glioma-bearing rats. Male Sprague–Dawley (SD) rats were subjected to tumor implantation in the right caudate putamen nucleus. At 17 days after tumor implantation, animals were exposed to an open field test. The numbers of crossings and rearings were used as measures of exploration processes. An input/output (I/O) curve was first determined using the measurements of field excitatory postsynaptic potential (fEPSP) slope in response to a series of stimulation intensities. The short-term potentiation (STP) and long-term potentiation (LTP) induced by high-frequency stimulation (HFS) in the CA1 region of the contralateral hippocampus to the tumor were recorded. The glutamate and γ-aminobutyric acid (GABA) content of contralateral hippocampus were quantified by high-performance liquid chromatography (HPLC). C6 glioma-bearing rats showed a trend for a rightward shift of input/output relationship and significant deficits in maintenance of STP and LTP. Quantitative analysis by HPLC of glutamate and γ-aminobutyric acid revealed that Glu concentration and Glu/GABA ratio were increased significantly in contralateral hippocampus, suggesting impairment of excitatory and inhibitory synaptic transmission. The results suggest that the neurocognitive deficits in C6 glioma-bearing rats may be mediated via profound changes in neuroplasticity and elevated Glu concentration and Glu/GABA ratio in hippocampus area of the brain.


C6 glioma model Cognitive deficit Long-term potentiation (LTP) High-performance liquid chromatography (HPLC) Glutamate 



This work was supported by grants from the National Natural Science Foundation of China (30870827, 31070964), the “111” Project (B08011) and TRPAFAT (10jczdjc19100).


  1. 1.
    Sathornsumetee S, Rich JN (2006) New treatment strategies for malignant gliomas. Expert Rev Anticancer Ther 6:1087–1104PubMedCrossRefGoogle Scholar
  2. 2.
    Kayl AE, Meyers CA (2003) Does brain tumor histology influence cognitive function? Neuro Oncol 5:255–260PubMedCrossRefGoogle Scholar
  3. 3.
    Taphoorn MJ, Klein M (2004) Cognitive deficits in adult patients with brain tumours. Lancet Neurol 3:159–168PubMedCrossRefGoogle Scholar
  4. 4.
    Foster TC (1999) Involvement of hippocampal synaptic plasticity in age-related memory decline. Brain Res Brain Res Rev 30:236–249PubMedCrossRefGoogle Scholar
  5. 5.
    Lante F, de Jesus Ferreira MC, Guiramand J, Recasens M, Vignes M (2006) Low-frequency stimulation induces a new form of LTP, metabotropic glutamate (mGlu5) receptor- and PKA-dependent, in the CA1 area of the rat hippocampus. Hippocampus 16:345–360PubMedCrossRefGoogle Scholar
  6. 6.
    Quan MN, Tian YT, Xu KH, Zhang T, Yang Z (2010) Post weaning social isolation influences spatial cognition, prefrontal cortical synaptic plasticity and hippocampal potassium ion channels in Wistar rats. Neuroscience 169:214–222PubMedCrossRefGoogle Scholar
  7. 7.
    Bliss TV, Lomo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232:331–356PubMedGoogle Scholar
  8. 8.
    Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39PubMedCrossRefGoogle Scholar
  9. 9.
    Malenka RC, Nicoll RA (1999) Long-term potentiation–a decade of progress? Science 285:1870–1874PubMedCrossRefGoogle Scholar
  10. 10.
    Martin SJ, Grimwood PD, Morris RG (2000) Synaptic plasticity and memory: an evaluation of the hypothesis. Annu Rev Neurosci 23:649–711PubMedCrossRefGoogle Scholar
  11. 11.
    Schmid AW, Lynch MA, Herron CE (2009) The effects of IL-1 receptor antagonist on beta amyloid mediated depression of LTP in the rat CA1 in vivo. Hippocampus 19:670–676PubMedCrossRefGoogle Scholar
  12. 12.
    Su Z, Han D, Sun B, Qiu J, Li Y, Li M, Zhang T, Yang Z (2009) Heat stress preconditioning improves cognitive outcome after diffuse axonal injury in rats. J Neurotrauma 26:1695–1706PubMedCrossRefGoogle Scholar
  13. 13.
    Bao G, Kang L, Li H, Li Y, Pu L, Xia P, Ma L, Pei G (2007) Morphine and heroin differentially modulate in vivo hippocampal LTP in opiate-dependent rat. Neuropsychopharmacology 32:1738–1749PubMedCrossRefGoogle Scholar
  14. 14.
    Zhang Y, Cai GE, Yang Q, Lu QC, Li ST, Ju G (2010) Time-dependent changes in learning ability and induction of long-term potentiation in the lithium-pilocarpine-induced epileptic mouse model. Epilepsy Behav 17:448–454PubMedCrossRefGoogle Scholar
  15. 15.
    de Oliveira MS, Cechim G, Braganhol E, Santos DG, Meurer L, de Castro CG Jr, Brunetto AL, Schwartsmann G, Battastini AM, Lenz G, Roesler R, Lenz G, Roesler R (2009) Anti-proliferative effect of the gastrin-release peptide receptor antagonist RC-3095 plus temozolomide in experimental glioblastoma models. J Neurooncol 93:191–201PubMedCrossRefGoogle Scholar
  16. 16.
    Cao J, Chen N, Xu T, Xu L (2004) Stress-facilitated LTD induces output plasticity through synchronized-spikes and spontaneous unitary discharges in the CA1 region of the hippocampus. Neurosci Res 49:229–239PubMedCrossRefGoogle Scholar
  17. 17.
    Leung LS (1980) Behavior-dependent evoked potentials in the hippocampal CA1 region of the rat. I. Correlation with behavior and EEG. Brain Res 198:95–117PubMedCrossRefGoogle Scholar
  18. 18.
    Carlsson G, Gullberg B, Hafstrom L (1983) Estimation of liver tumor volume using different formulas—an experimental study in rats. J Cancer Res Clin Oncol 105:20–23PubMedCrossRefGoogle Scholar
  19. 19.
    Leong AS, Milios J (1990) Accelerated immunohistochemical staining by microwaves. J Pathol 161:327–334PubMedCrossRefGoogle Scholar
  20. 20.
    Kaye AH, Morstyn G, Gardner I, Pyke K (1986) Development of a xenograft glioma model in mouse brain. Cancer Res 46:1367–1373PubMedGoogle Scholar
  21. 21.
    Grobben B, De Deyn PP, Slegers H (2002) Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion. Cell Tissue Res 310:257–270PubMedCrossRefGoogle Scholar
  22. 22.
    Hasselmo ME (1995) Neuromodulation and cortical function: modeling the physiological basis of behavior. Behav Brain Res 67:1–27PubMedCrossRefGoogle Scholar
  23. 23.
    VanElzakker M, Fevurly RD, Breindel T, Spencer RL (2008) Environmental novelty is associated with a selective increase in Fos expression in the output elements of the hippocampal formation and the perirhinal cortex. Learn Mem 15:899–908PubMedCrossRefGoogle Scholar
  24. 24.
    Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21PubMedCrossRefGoogle Scholar
  25. 25.
    Moser MB, Moser EI (2000) Pretraining and the function of hippocampal long-term potentiation. Neuron 26:559–561PubMedCrossRefGoogle Scholar
  26. 26.
    Cooke SF, Bliss TV (2006) Plasticity in the human central nervous system. Brain 129:1659–1673PubMedCrossRefGoogle Scholar
  27. 27.
    Albensi BC, Oliver DR, Toupin J, Odero G (2007) Electrical stimulation protocols for hippocampal synaptic plasticity and neuronal hyper-excitability: are they effective or relevant? Exp Neurol 204:1–13PubMedCrossRefGoogle Scholar
  28. 28.
    Yoon KW (1995) Glutamate effect on synaptic transmission mediates neurotoxicity in dissociated rat hippocampal neurons. Brain Res 669:320–324PubMedCrossRefGoogle Scholar
  29. 29.
    Olney JW, Ho OL, Rhee V (1971) Cytotoxic effects of acidic and sulphur containing amino acids on the infant mouse central nervous system. Exp Brain Res 14:61–76PubMedCrossRefGoogle Scholar
  30. 30.
    Klegeris A, Walker DG, McGeer PL (1997) Regulation of glutamate in cultures of human monocytic THP-1 and astrocytoma U-373 MG cells. J Neuroimmunol 78:152–161PubMedCrossRefGoogle Scholar
  31. 31.
    Behrens PF, Langemann H, Strohschein R, Draeger J, Hennig J (2000) Extracellular glutamate and other metabolites in and around RG2 rat glioma: an intracerebral microdialysis study. J Neurooncol 47:11–22PubMedCrossRefGoogle Scholar
  32. 32.
    Marder CP, Buonomano DV (2003) Differential effects of short- and long-term potentiation on cell firing in the CA1 region of the hippocampus. J Neurosci 23:112–121PubMedGoogle Scholar
  33. 33.
    Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  1. 1.College of Life Science and Key Laboratory of Bioactive Materials, Ministry of EducationNankai UniversityTianjinChina
  2. 2.College of MedicineNankai UniversityTianjinChina

Personalised recommendations