Changes in the glutamate/gaba system in the hippocampus of rats with age and during the Alzheimer’s disease signs development

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

GABA and glutamate are the most abundant neurotransmitters in the CNS and play a pivotal part in synaptic stability/plasticity. Glutamate and GABA homeostasis is important for healthy aging and reducing the risk of various neurological diseases, while long-term imbalance can contribute to the development of neurodegenerative disorders, including Alzheimer’s disease (AD). Its normalization discussed as a promising strategy for the prevention and/or treatment of AD, however, data on changes in the GABAergic and glutamatergic systems in with age, as well as in the dynamics of AD development, are limited. It is not clear whether the imbalance of the excitatory/inhibitory systems is a cause or a consequence of the development of the disease. Here we analyzed age-related alterations of the expression of glutamate, GABA, and enzymes that synthesize them (glutaminase, glutamine synthetase, GABA-T, and GAD67), transporters (GLAST, GLT-1, and GAT1), and relevant receptors (GluA1, NMDAR1, NMDA2B, and GABAAr1) in the whole hippocampus of Wistar rats and of senescence-accelerated OXYS rats, a model of the most common (> 95%) sporadic AD. Our results suggest that there is a decline of glutamate and GABA signaling with aging in the hippocampus of the both rat strains. However, we have not identified significant changes or compensatory enhancements in this system in the hippocampus of OXYS rats during development of neurodegenerative processes that are characteristic of AD.

About the authors

A. O Burnyasheva

Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Siberian Branch of the Russian Academy of Sciences

=630090 Novosibirsk, Russia

N. A Stefanova

Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Siberian Branch of the Russian Academy of Sciences

=630090 Novosibirsk, Russia

N. G Kolosova

Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Siberian Branch of the Russian Academy of Sciences

Email: kolosova@bionet.nsc.ru
=630090 Novosibirsk, Russia

D. V Telegina

Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Siberian Branch of the Russian Academy of Sciences

=630090 Novosibirsk, Russia

References

  1. Wang, R., and Reddy, P. H. (2017) Role of glutamate and NMDA receptors in Alzheimer's disease, J. Alzheimers Dis., 57, 1041-1048, doi: 10.3233/JAD-160763.
  2. Selkoe, D. J., and Hardy, J. (2016) The amyloid hypothesis of Alzheimer's disease at 25 years, EMBO Mol. Med., 8, 595-608, doi: 10.15252/emmm.201606210.
  3. Wyss-Coray, T. (2016) Ageing, neurodegeneration and brain rejuvenation, Nature, 539, 180-186, doi: 10.1038/nature20411.
  4. Polanco, J. C., Li, C., Bodea, L. G., Martinez-Marmol, R., Meunier, F. A., and Götz, J. (2017) Amyloid-β and tau complexity - towards improved biomarkers and targeted therapies, Nat. Rev. Neurol., 14, 22-39, doi: 10.1038/nrneurol.2017.162.
  5. Cox, M. F., Hascup, E. R., Bartke, A., and Hascup, K. N. (2022) Friend or foe? Defining the role of glutamate in aging and Alzheimer's disease, Front. Aging, 3, 929474, doi: 10.3389/fragi.2022.929474.
  6. Hampe, C. S., Mitoma, H., and Manto, M. (2018) GABA and glutamate: their transmitter role in the CNS and pancreatic islets, in GABA and Glutamate - New Developments in Neurotransmission Research, IntechOpen, Book Chapter 5, pp. 65-90, doi: 10.5772/intechopen.70958.
  7. Sears, S. M. S., and Hewett, S. J. (2021) Influence of glutamate and GABA transport on brain excitatory/inhibitory balance, Exp. Biol. Med. (Maywood), 246, 1069-1083, doi: 10.1177/1535370221989263.
  8. Kolosova, N. G., Stefanova, N. A., Korbolina, E. E., Fursova, A. Z., and Kozhevnikova, O. S. (2014) Senescence-accelerated OXYS rats: a genetic model of premature aging and age-related diseases, Adv. Gerontol., 27, 336-340, doi: 10.1134/S2079057014040146.
  9. Stefanova, N. A., Muraleva, N. A., Korbolina, E. E., Kiseleva, E., Maksimova, K. Y., and Kolosova, N. G. (2015) Amyloid accumulation is a late event in sporadic Alzheimer's disease-like pathology in nontransgenic rats, Oncotarget, 6, 1396-1413, doi: 10.18632/ONCOTARGET.2751.
  10. Kolosova, N. G., Kozhevnikova, O. S., Muraleva, N. A., Rudnitskaya, E. A., Rumyantseva, Y. V., Stefanova, N. A., Telegina, D. V., Tyumentsev, M. A., Fursova, A. Z. (2022) SkQ1 as a tool for controlling accelerated senescence program: experiments with OXYS rats, Biochemistry (Moscow), 87, 1552-1562, doi: 10.1134/S0006297922120124.
  11. Stefanova, N. A., Maksimova, K. Y., Kiseleva, E., Rudnitskaya, E. A., Muraleva, N. A., and Kolosova, N. G. (2015) Melatonin attenuates impairments of structural hippocampal neuroplasticity in OXYS rats during active progression of Alzheimer's disease-like pathology, J. Pineal. Res., 59, 163-177, doi: 10.1111/JPI.12248.
  12. Telegina, D. V., Antonenko, A. K., Fursova, A. Z., and Kolosova, N. G. (2022) The glutamate/GABA System in the retina of male rats: effects of aging, neurodegeneration, and supplementation with melatonin and antioxidant SkQ1, Biogerontology, 23, 571-585, doi: 10.1007/s10522-022-09983-w.
  13. Stefanova, N. A., and Kolosova, N. G. (2023) The rat brain transcriptome: from infancy to aging and sporadic Alzheimer's disease-like pathology, Int. J. Mol. Sci., 24, 1462, doi: 10.3390/ijms24021462.
  14. Stefanova, N. A., Maksimova, K. Y., Rudnitskaya, E. A., Muraleva, N. A., and Kolosova, N. G. (2018) Association of cerebrovascular dysfunction with the development of Alzheimer's disease-like pathology in OXYS rats, BMC Genomics, 19, 51-63, doi: 10.1186/S12864-018-4480-9.
  15. Magi, S., Piccirillo, S., Amoroso, S., and Lariccia, V. (2019) Excitatory amino acid transporters (EAATs): glutamate transport and beyond, Int. J. Mol. Sci., 20, 5674, doi: 10.3390/ijms20225674.
  16. Pajarillo, E., Rizor, A., Lee, J., Aschner, M., Lee, E. (2019) The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics, Neuropharmacology, 161, 1-37, doi: 10.1016/j.neuropharm.2019.03.002.
  17. Snytnikova, O., Telegina, D., Savina, E., Tsentalovich, Y., and Kolosova, N. (2023) Quantitative metabolomic analysis of the rat hippocampus: effects of age and of the development of Alzheimer's disease-like pathology, J. Alzheimer's Disease, doi: 10.3233/JAD-230706, in press.
  18. Schubert, F., Gallinat, J., Seifert, F., and Rinneberg, H. (2004) Glutamate concentrations in human brain using single voxel proton magnetic resonance spectroscopy at 3 Tesla, NeuroImage, 21, 1762-1771, doi: 10.1016/j.neuroimage.2003.11.014.
  19. Kaiser, L.G., Schuff, N., Cashdollar, N., and Weiner, M. W. (2005) Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T, Neurobiol. Aging, 26, 665-672, doi: 10.1016/j.neurobiolaging.2004.07.001.
  20. Chang, L., Jiang, C. S., and Ernst, T. (2009) Effects of age and sex on brain glutamate and other metabolites, Magn. Reson. Imaging, 27, 142-145, doi: 10.1016/j.mri.2008.06.002.21.
  21. Huang, D., Liu, D., Yin, J., Qian, T., Shrestha, S., and Ni, H. (2017) Glutamate-glutamine and GABA in brain of normal aged and patients with cognitive impairment, Eur. Radiol., 27, 2698-2705, doi: 10.1007/S00330-016-4669-8.
  22. Rozycka, A., Charzynska, A., Misiewicz, Z., Maciej Stepniewski, T., Sobolewska, A., Kossut, M., and Liguz-Lecznar, M. (2019) Glutamate, GABA, and presynaptic markers involved in neurotransmission are differently affected by age in distinct mouse brain regions, ACS Chem. Neurosci., 10, 4449-4461, doi: 10.1021/acschemneuro.9b00220.
  23. Segovia, G., Porras, A., Del Arco, A., and Mora, F. (2001) Glutamatergic neurotransmission in aging: a critical perspective, Mech. Ageing Dev., 122, 1-29, doi: 10.1016/S0047-6374(00)00225-6.
  24. Dong, Y., and Brewer, G. J. (2019) Global metabolic shifts in age and Alzheimer's disease mouse brains pivot at NAD+/NADH redox sites, J. Alzheimer's Dis., 71, 119-140, doi: 10.3233/JAD-190408.
  25. Mira, R. G., and Cerpa, W. (2020) Building a bridge between NMDAR-mediatedexcitotoxicity and mitochondrial dysfunction in chronic and acute diseases, Cell. Mol. Neurobiol., 41, 1413-1430, doi: 10.1007/S10571-020-00924-0.
  26. Rodríguez-Giraldo, M., González-Reyes, R. E., Ramírez-Guerrero, S., Bonilla-Trilleras, C. E., Guardo-Maya, S., and Nava-Mesa, M. O. (2022) Astrocytes as a therapeutic target in Alzheimer's disease-comprehensive review and recent developments, Int. J. Mol. Sci., 23, 13630, doi: 10.3390/ijms232113630.
  27. Yeung, J. H. Y., Palpagama, T. H., Wood, O. W. G., Turner, C., Waldvogel, H. J., Faull, R. L. M., and Kwakowsky, A. (2021) EAAT2 expression in the hippocampus, subiculum, entorhinal cortex and superior temporal gyrus in Alzheimer's disease, Front. Cell. Neurosci., 15, 702824, doi: 10.3389/fncel.2021.702824.
  28. Babaei, P. (2021) NMDA and AMPA receptors dysregulation in Alzheimer's disease, Eur. J. Pharmacol., 908, 174310, doi: 10.1016/j.ejphar.2021.174310.
  29. Kumar, A. (2015) NMDA receptor function during senescence: implication on cognitive performance, Front. Neurosci., 9, 473, doi: 10.3389/fnins.2015.00473.
  30. Kumar, A., and Foster, T. C. (2018) Alteration in NMDA receptor mediated glutamatergic neurotransmission in the hippocampus during senescence, Neurochem. Res., 44, 38-48, doi: 10.1007/S11064-018-2634-4.
  31. Avila, J., Llorens-Martín, M., Pallas-Bazarra, N., Bolos, M., Perea, J. R., Rodríguez-Matellan, A., and Hernandez, F. (2017) Cognitive decline in neuronal aging and Alzheimer's disease: role of NMDA receptors and associated proteins, Front. Neurosci., 11, 626, doi: 10.3389/fnins.2017.00626.
  32. Cercato, M. C., Vázquez, C. A., Kornisiuk, E., Aguirre, A. I., Colettis, N., Snitcofsky, M., Jerusalinsky, D. A., and Baez, M. V. (2017) GluN1 and GluN2A NMDA receptor subunits increase in the hippocampus during memory consolidation in the rat, Front. Behav. Neurosci., 10, 242, doi: 10.3389/fnbeh.2016.00242.
  33. Ge, Y., and Wang, Y. T. (2023) GluN2B-containing NMDARs in the mammalian brain: pharmacology, physiology, and pathology, Front. Mol. Neurosci., 16, 1190324, doi: 10.3389/fnmol.2023.1190324.
  34. Yeung, J. H. Y., Walby, J. L., Palpagama, T. H., Turner, C., Waldvogel, H. J., Faull, R. L. M., and Kwakowsky, A. (2021) Glutamatergic receptor expression changes in the Alzheimer's disease hippocampus and entorhinal cortex, Brain Pathol., 31, e13005, doi: 10.1111/BPA.13005.
  35. Qu, W., Yuan, B., Liu, J., Liu, Q., Zhang, X., Cui, R., Yang, W., and Li, B. (2021) Emerging role of AMPA receptor subunit GluA1 in synaptic plasticity: implications for Alzheimer's disease, Cell Prolif., 54, e12959, doi: 10.1111/cpr.12959.
  36. Li, Y., Sun, H., Chen, Z., Xu, H., Bu, G., and Zheng, H. (2016) Implications of GABAergic neurotransmission in Alzheimer's disease, Front. Aging Neurosci., 8, 31, doi: 10.3389/fnagi.2016.00031.
  37. Bi, D., Wen, L., Wu, Z., and Shen, Y. (2020) GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease, Alzheimers Dement., 16, 1312-1329, doi: 10.1002/alz.12088.
  38. Lee, S. E., Lee, Y., and Lee, G. H. (2019) The regulation of glutamic acid decarboxylases in GABA neurotransmission in the brain, Arch. Pharm. Res., 42, 1031-1039, doi: 10.1007/s12272-019-01196-z.
  39. Chattopadhyaya, B., Di Cristo, G., Wu, C. Z., Knott, G., Kuhlman, S., Fu, Y., Palmiter, R. D., and Huang, Z. J. (2007) GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex, Neuron, 54, 889-903, doi: 10.1016/j.neuron.2007.05.015.
  40. Lau, C. G., and Murthy, V. N. (2012) Activity-dependent regulation of inhibition via GAD67, J. Neurosci., 32, 8521-8531, doi: 10.1523/JNEUROSCI.1245-12.2012.
  41. Sandhu, K. V., Lang, D., Müller, B., Nullmeier, S., Yanagawa, Y., Schwegler, H., and Stork, O. (2014) Glutamic acid decarboxylase 67 haplodeficiency impairs social behavior in mice, Genes Brain Behav., 13, 439-450, doi: 10.1111/GBB.12131.
  42. Kash, S. F., Johnson, R. S., Tecott, L. H., Noebels, J. L., Mayfield, R. D., Hanahan, D., and Baekkeskov, S. (1997) Epilepsy in mice deficient in the 65-KDa isoform of glutamic acid decarboxylase, Proc. Natl. Acad. Sci. USA, 94, 14060-14065, doi: 10.1073/PNAS.94.25.14060.
  43. Toritsuka, M., Yoshino, H., Makinodan, M., Ikawa, D., Kimoto, S., Yamamuro, K., Okamura, K., Akamatsu, W., Okada, Y., Matsumoto, T., Hashimoto, K., Ogawa, Y., Saito, Y., Watanabe, K., Aoki, C., Takada, R., Fukami, S. I., Hamano-Iwasa, K., Okano, H., and Kishimoto, T. (2021) Developmental dysregulation of excitatory-to-inhibitory GABA-polarity switch may underlie schizophrenia pathology: a monozygotic-twin discordant case analysis in human IPS cell-derived neurons, Neurochem. Int., 150, e105179, doi: 10.1016/J.NEUINT.2021.105179.
  44. Benes, F. M., Lim, B., Matzilevich, D., Walsh, J. P., Subburaju, S., and Minns, M. (2007) Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars, Proc. Natl. Acad. Sci. USA, 104, 10164-10169, doi: 10.1073/pnas.0703806104.
  45. Lanoue, A. C., Dumitriu, A., Myers, R. H., Soghomonian, J. J. (2010) Decreased glutamic acid decarboxylase MRNA expression in prefrontal cortex in Parkinson's disease, Exp. Neurol., 226, 207-217, doi: 10.1016/j.expneurol.2010.09.001.
  46. Wang, Y., Wu, Z., Bai, Y. T., Wu, G. Y., and Chen, G. (2017) Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer's disease, Mol. Neurodegener., 12, 73, doi: 10.1186/s13024-017-0213-9.
  47. Ethiraj, J., Palpagama, T. H., Turner, C., van der Werf, B., Waldvogel, H. J., Faull, R. L. M., and Kwakowsky, A. (2021) The effect of age and sex on the expression of GABA signaling components in the human hippocampus and entorhinal cortex, Sci. Rep., 11, 21470, doi: 10.1038/s41598-021-00792-8.
  48. Krantic, S., Isorce, N., Mechawar, N., Davoli, M. A., Vignault, E., Albuquerque, M., Chabot, J. G., Moyse, E., Chauvin, J. P., Aubert, I., McLaurin, J., and Quirion, R. (2012) Hippocampal GABAergic neurons are susceptible to amyloid-β Toxicity in vitro and are decreased in number in the Alzheimer's disease TgCRND8 mouse model, J. Alzheimers Dis., 29, 293-308, doi: 10.3233/JAD-2011-110830.
  49. Ulrich, D. (2015) Amyloid-β impairs synaptic inhibition via GABAA receptor endocytosis, J. Neurosci., 35, 9205-9210, doi: 10.1523/JNEUROSCI.0950-15.2015.
  50. Palpagama, T. H., Sagniez, M., Kim, S., Waldvogel, H. J., Faull, R. L., and Kwakowsky, A. (2019) GABAA receptors are well preserved in the hippocampus of aged mice, eNeuro, 6, 1-13, doi: 10.1523/ENEURO.0496-18.2019.
  51. Rissman, R. A., and Mobley, W. C. (2011) Implications for treatment: GABAA receptors in aging, down syndrome and Alzheimer's disease, J. Neurochem., 117, 613-622, doi: 10.1111/J.1471-4159.2011.07237.X.
  52. Stefanova, N. A., Kozhevnikova, O. S., Vitovtov, A. O., Maksimova, K. Y., Logvinov, S. V., Rudnitskaya, E. A., Korbolina, E. E., Muraleva, N. A., and Kolosova, N. G. (2014) Senescence-accelerated OXYS rats: a model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease, Cell Cycle, 13, 898-909, doi: 10.4161/CC.28255.
  53. Neff, R. A., Wang, M., Vatansever, S., Guo, L., Ming, C., Wang, Q., Wang, E., Horgusluoglu-Moloch, E., Song, W. M., Li, A., Castranio, E. L., Tcw, J., Ho, L., Goate, A., Fossati, V., Noggle, S., Gandy, S., Ehrlich, M. E., Katsel, P., Schadt, E., Cai, D., Brennand, K. J., Haroutunian, V., and Zhang, B. (2021) Molecular subtyping of Alzheimer's disease using RNA sequencing data reveals novel mechanisms and targets, Sci. Adv., 7, eabb5398, doi: 10.1126/sciadv.abb5398.

Copyright (c) 2023 Russian Academy of Sciences

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies