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Expression Changes of NMDA and AMPA Receptor Subunits in the Hippocampus in rats with Diabetes Induced by Streptozotocin Coupled with Memory Impairment

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Abstract

Cognitive impairment in diabetes (CID) is a severe chronic complication of diabetes mellitus (DM). It has been hypothesized that diabetes can lead to cognitive dysfunction due to expression changes of excitatory neurotransmission mediated by N-methyl-d-aspartate receptors (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR); however, the pathogenesis involved in this has not been fully understood, especially at early phase of DM. Here, we sought to determine the cognitive changes and aim to correlate this with the expression changes of NMDAR and AMPAR of glutamate signaling pathways in the rat hippocampus from early phase of DM and in the course of the disease progression. By Western blot analysis and immunofluorescence labeling, the hippocampus in diabetic rats showed a significant increase in protein expression NMDAR subunits NR1, NR2A and NR2B and AMPAR subunit GluR1. Along with this, behavioral test by Morris water maze showed a significant decline in their performance when compared with the control rats. It is suggested that NR1, NR2A, NR2B and GluR1are involved in learning and memory and that their expression alterations maybe correlated with the occurrence and development of CID in diabetic rats induced by streptozotocin.

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Abbreviations

CID:

Cognitive impairment in diabetes

Glu:

Glutamate (glutamic acid)

GluR:

Glu receptor

mGluR:

Metabotropic glutamate receptors

iGluR:

Ionotropic glutamate receptor

NMDA:

N-methyl-d-aspartate

NMDAR:

NMDA glutamate receptor

NR1,:

NMDAR subunits 1

NR2A:

NMDAR subunits 2A

NR2B:

NMDAR subunits 2B

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

AMPAR:

AMPA glutamate receptor

DM:

Diabetes mellitus

LTP:

Long-term potentiation

LTD:

Long-term depression

STZ:

Streptozotocin

H&E:

Hematoxylin-eosin

AD:

Alzheimer’s disease

References

  1. Jing YH, Chen KH, Kuo PC, Pao CC, Chen JK (2013) Neurodegeneration in streptozotocin-induced diabetic rats is attenuated by treatment with resveratrol. Neuroendocrinology 98(2):116–127

    Article  CAS  PubMed  Google Scholar 

  2. Cukierman T, Gerstein HC, Williamson JD (2005) Cognitive decline and dementia in diabetes–systematic overview of prospective observational studies. Diabetologia 48(12):2460–2469

    Article  CAS  PubMed  Google Scholar 

  3. Grimmig B, Kim SH, Nash K, Bickford PC, Douglas R, Shytle (2017) Neuroprotective mechanisms of astaxanthin: a potential therapeutic role in preserving cognitive function in age and neurodegeneration. GeroScience 39(1):19–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Christman AL, Vannorsdall TD, Pearlson GD, Hill-Briggs F, Schretlen DJ (2010) Cranial volume, mild cognitive deficits, and functional limitations associated with diabetes in a community sample. Arch Clin Neuropsychol 25(1):49–59

    Article  PubMed  Google Scholar 

  5. Hovelso N, Sotty F, Montezinho LP, Pinheiro PS, Herrik KF, Mork A (2012) Therapeutic potential of metabotropic glutamate receptor modulators. Curr Neuropharmacol 10(1):12–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fitzjohn S, Bashir Z, Farrow P (2016) Group I mGluR induced LTD of NMDAR-synaptic transmission at the schaffer collateral but not temperoammonic input to CA1. Curr Neuropharmacol 14(5):435–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Coultrap SJ, Bickford PC, Browning MD (2008) Blueberry-enriched diet ameliorates age-related declines in NMDA receptor-dependent LTP. Age 30(4):263–272

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wang Z, Ruan Q, Wang D (2005) Different effects of intracochlear sensory and neuronal injury stimulation on expression of synaptic N-methyl-D-aspartate receptors in the auditory cortex of rats in vivo. Acta Otolaryngol 125(11):1145–1151

    Article  CAS  PubMed  Google Scholar 

  9. Le Bail M, Martineau M, Sacchi S, Yatsenko N, Radzishevsky I, Conrod S, Ait Ouares K, Wolosker H, Pollegioni L, Billard JM, Mothet JP, Identity of the NMDA receptor coagonist is synapse specific and developmentally regulated in the hippocampus. Proc Natl Acad Sci USA 112(2) (2015) E204–E213

    Google Scholar 

  10. Matsunaga Y, Negishi T, Hatakeyama A, Kawagoe Y, Sawano E, Tashiro T (2016) Impairment of synaptic development in the hippocampus of diabetic Goto-Kakizaki rats. Int J Dev Neurosci 53:58–67

    Article  CAS  PubMed  Google Scholar 

  11. Flores-Soto ME, Chaparro-Huerta V, Escoto-Delgadillo M, Vazquez-Valls E, Gonzalez-Castaneda RE, Beas-Zarate C (2012) Structure and function of NMDA-type glutamate receptor subunits]. Neurologia 27(5):301–310

    Article  CAS  PubMed  Google Scholar 

  12. Park CS, Elgersma Y, Grant SG, Morrison JH (2008) alpha-Isoform of calcium-calmodulin-dependent protein kinase II and postsynaptic density protein 95 differentially regulate synaptic expression of NR2A- and NR2B-containing N-methyl-d-aspartate receptors in hippocampus. Neuroscience 151(1):43–55

    Article  CAS  PubMed  Google Scholar 

  13. Kopp C, Longordo F, Luthi A (2007) Experience-dependent changes in NMDA receptor composition at mature central synapses. Neuropharmacology 53(1):1–9

    Article  CAS  PubMed  Google Scholar 

  14. Sanderson DJ, Good MA, Seeburg PH, Sprengel R, Rawlins JN, Bannerman DM (2008) The role of the GluR-A (GluR1) AMPA receptor subunit in learning and memory. Prog Brain Res 169:159–178

    Article  CAS  PubMed  Google Scholar 

  15. Schmitt WB, Sprengel R, Mack V, Draft RW, Seeburg PH, Deacon RM, Rawlins JN, Bannerman DM (2005) Restoration of spatial working memory by genetic rescue of GluR-A-deficient mice. Nat Neurosci 8(3):270–272

    Article  CAS  PubMed  Google Scholar 

  16. Sanderson DJ, Gray A, Simon A, Taylor AM, Deacon RM, Seeburg PH, Sprengel R, Good MA, Rawlins JN, Bannerman DM (2007) Deletion of glutamate receptor-A (GluR-A) AMPA receptor subunits impairs one-trial spatial memory. Behav Neurosci 121(3):559–569

    Article  CAS  PubMed  Google Scholar 

  17. Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52(5):831–843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Patten SA, Ali DW, (2009) PKCgamma-induced trafficking of AMPA receptors in embryonic zebrafish depends on NSF and PICK1. Proc Natl Acad Sci USA 106(16) 6796–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Block ML, Hong JS (2007) Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochem Soc Trans 35:1127–1132

    Article  CAS  PubMed  Google Scholar 

  20. Li ZG, Zhang W, Grunberger G, Sima AA (2002) Hippocampal neuronal apoptosis in type 1 diabetes. Brain Res 946(2):221–231

    Article  CAS  PubMed  Google Scholar 

  21. Wei M, Ong L, Smith MT, Ross FB, Schmid K, Hoey AJ, Burstow D, Brown L (2003) The streptozotocin-diabetic rat as a model of the chronic complications of human diabetes. Heart Lung Circ 12(1):44–50

    Article  PubMed  Google Scholar 

  22. Szkudelski T (2001) The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 50(6):537–546

    CAS  PubMed  Google Scholar 

  23. Matteucci E, Giampietro O (2008) Proposal open for discussion: defining agreed diagnostic procedures in experimental diabetes research. J Ethnopharmacol 115(2):163–172

    Article  PubMed  Google Scholar 

  24. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1(2):848–858

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ma S, Xu S, Liu B, Li J, Feng N, Wang L, Wang X (2009) Long-term treatment of l-3-n-butylphthalide attenuated neurodegenerative changes in aged rats. Naunyn-Schmiedeberg’s Arch Pharmacol 379(6):565–574

    Article  CAS  Google Scholar 

  26. Wu C, Luk WP, Gillis J, Skinner F, Zhang L (2005) Size does matter: generation of intrinsic network rhythms in thick mouse hippocampal slices. J Neurophysiol 93(4):2302–2317

    Article  PubMed  Google Scholar 

  27. Hardigan T, Ward R, Ergul A (2016) Cerebrovascular complications of diabetes: focus on cognitive dysfunction. Clin Sci 130(20):1807–1822

    Article  CAS  Google Scholar 

  28. McCrimmon RJ, Ryan CM, Frier BM (2012) Diabetes and cognitive dysfunction. Lancet 379(9833):2291–2299

    Article  PubMed  Google Scholar 

  29. Zilliox LA, Chadrasekaran K, Kwan JY, Russell JW (2016) Diabetes cognitive impairment. Curr Diab Rep 16(9):87

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Biessels GJ, Reagan LP (2015) Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci 16(11):660–671

    Article  CAS  PubMed  Google Scholar 

  31. Zhang S, Li H, Zhang L, Li J, Wang R, Wang M (2017) Effects of troxerutin on cognitive deficits and glutamate cysteine ligase subunits in the hippocampus of streptozotocin-induced type 1 diabetes mellitus rats. Brain Res 1657:355–360

    Article  CAS  PubMed  Google Scholar 

  32. Ma LY, Fei YL, Wang XY, Wu SD, Du JH, Zhu M, Jin L, Li M, Li HL, Zhai JJ, Ji LP, Ma RR, Liu SF, Li M, Ma L, Ma XR, Qu QM, Lv YL (2017) The research on the relationship of rage, LRP-1, and Abeta accumulation in the hippocampus, prefrontal lobe, and amygdala of STZ-induced diabetic rats. J Mol Neurosci 62(1):1–10

    Article  CAS  PubMed  Google Scholar 

  33. Foghi AS K, Diabetes mellitus type1 and neuronal degeneration in ventral and dorsal hippocampus., Iran J Pathol 9(1) (2014)

  34. Park YM, Lee BG, Park SH, Oh HG, Kang YG, Kim OJ, Kwon LS, Kim YP, Choi MH, Jeong YS, Oh J, Lee HY (2015) Prolonged oral administration of Gastrodia elata extract improves spatial learning and memory of scopolamine-treated rats. Lab Anim Res 31(2):69–77

    Article  PubMed  PubMed Central  Google Scholar 

  35. D’Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Rev 36(1):60–90

    Article  PubMed  Google Scholar 

  36. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27(11):2866–2875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Boehm J, Kang MG, Johnson RC, Esteban J, Huganir RL, Malinow R (2006) Synaptic incorporation of AMPA receptors during LTP is controlled by a PKC phosphorylation site on GluR1. Neuron 51(2):213–225

    Article  CAS  PubMed  Google Scholar 

  38. Beckhauser TF, Francis-Oliveira J, De Pasquale R (2016) Reactive oxygen species: physiological and physiopathological effects on synaptic plasticity. J Exp Neurosci 10(Suppl 1):23–48

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Hardingham GE, Fukunaga Y, Bading H (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 5(5):405–414

    Article  CAS  PubMed  Google Scholar 

  40. Mathern GW, Pretorius JK, Mendoza D, Leite JP, Chimelli L, Born DE, Fried I, Assirati JA, Ojemann GA, Adelson PD, Cahan LD, Kornblum HI (1999) Hippocampal N-methyl-D-aspartate receptor subunit mRNA levels in temporal lobe epilepsy patients. Ann Neurol 46(3):343–358

    Article  CAS  PubMed  Google Scholar 

  41. Sanz-Clemente A, Nicoll RA, Roche KW (2013) Diversity in NMDA receptor composition: many regulators, many consequences, the neuroscientist: a review journal bringing neurobiology. Neurol Psychiatry 19(1):62–75

    CAS  Google Scholar 

  42. Zhang J, Wang C, Deng T, Xue Z, Chen X, Chang L, Wang Q (2013) The preventive effect of NR2B and NR2D-containing NMDAR antagonists on Abeta-induced LTP disruption in the dentate gyrus of rats. Metab Brain Dis 28(4):697–704

    Article  CAS  PubMed  Google Scholar 

  43. Ma SH, Zhuang QX, Shen WX, Peng YP, Qiu YH (2015) Interleukin-6 reduces NMDAR-mediated cytosolic Ca overload and neuronal death via JAK/CaN signaling. Cell Calcium 25(3):286–295

    Google Scholar 

  44. Wang YM, Liu YP, Cao K, Qin BW, Shang YZ (2012) Effects of flavonoids isolated from Scutellaria stem and leaf on expression of NMDAR and VEGF in chronic cerebral ischemia rats. Chin J Pathophysiol 28(2):353–357

    CAS  Google Scholar 

  45. Zhao RZ, Tang QS, Tian Q, Li XL (2012) Expressions of brain NR1 and NR2B of NMDA receptor in depressive rats and interference effect of Chinese medicinals. J Beijing Univ Tradit Chin Med 35(6):383–385

    Google Scholar 

  46. Berretta N, Ledonne A, Mango D, Bernardi G, Mercuri NB (2012) Hippocampus versus entorhinal cortex decoupling by an NR2 subunit-specific block of NMDA receptors in a rat in vitro model of temporal lobe epilepsy. Epilepsia 53(5):e80–e84

    Article  CAS  PubMed  Google Scholar 

  47. Zhao LX, Ge YH, Xiong CH, Tang L, Yan YH, Law PY, Qiu Y, Chen HZ, M1 muscarinic receptor facilitates cognitive function by interplay with AMPA receptor GluA1 subunit, FASEB J (2018) fj201800029R

  48. Kessels HW, Malinow R (2009) Synaptic AMPA receptor plasticity and behavior. Neuron 61(3):340–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported in part by grants (81760149, 81360176, 81200840 and 81260361) from the National Natural Sciences Foundation of China, a grant (2013HB078) from the Department of Science and Technology of Yunnan Province, the grants (2017FE468 (-171) and 2017FE468) from the Joint Special Funds for the Department of Science and Technology of Yunnan Province-Kunming Medical University, and the grant (2018JS156) from Yunnan provincial Education Commission.

Author’s Contributions

YYZ is the corresponding author, FW and ZHY are the co-corresponding author of this article. XPW, PY and JL contributed equally to this work. YYZ, FW and ZHY designed the project, contributed to the analysis of data and finalization of the manuscript. XPW conducted most of the experiments. PY conducted part of experiments and prepared the first draft of the manuscript. JL conducted part of experiments and participated in editing the manuscript. LZ guided the Morris Water Maze testing and analysis of data. ZYQ carried out the paraffin embedding, sectioning, H&E and immunofluorescence staining. YJH helped with removal of tissue samples and took care of the experimental rats. QW revised the manuscript. ZHM, XJL and XW carried out part of analysis of data and editing the manuscript, QW revised the manuscript. All authors have read and approved the final version of the manuscript.

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Author notes

  1. Xiao-Peng Wang, Pin Ye and Jiao Lv have contributed equally to the work

Authors and Affiliations

  1. Department of Pathology and Pathophysiology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People’s Republic of China

    Xiao-Peng Wang, Jiao Lv, Yong-Jie Huang, Zhi-Hao Mu, Xie Wang, Xin-jie Liu, Zhi-Hong Yang, Fang Wang & Ying-Ying Zou

  2. Department of Human Anatomy and Histology/Embryology, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People’s Republic of China

    Pin Ye

  3. The Key Laboratory of Stem Cell and Regenerative Medicine of Yunnan Province, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People’s Republic of China

    Lei Zhou

  4. Department of Morphological Laboratory, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People’s Republic of China

    Zhong-Yi Qian

  5. Institute of Neuroregeneration & Neurorehabilitation, Department of Neurosurgery of the Affiliated Hospital, Qingdao University, Qingdao, 266071, People’s Republic of China

    Qi Wan

  6. Drug Rehabilitation Center, Huaixian Street, Datong, 038300, Shanxi, People’s Republic of China

    Xiao-Peng Wang

  7. Emergency Department, First Affiliated Hospital of Kunming, Medical University, 295 Xi Chang Road, Kunming, 650032, People’s Republic of China

    Yong-Jie Huang

  8. Undergraduate of Batch 2016 in Clinical Medicine Major, Faculty of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Kunming, 650500, People’s Republic of China

    Xin-jie Liu

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  1. Xiao-Peng Wang
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Correspondence to Zhi-Hong Yang, Fang Wang or Ying-Ying Zou.

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Wang, XP., Ye, P., Lv, J. et al. Expression Changes of NMDA and AMPA Receptor Subunits in the Hippocampus in rats with Diabetes Induced by Streptozotocin Coupled with Memory Impairment. Neurochem Res 44, 978–993 (2019). https://doi.org/10.1007/s11064-019-02733-4

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