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Study of the Mechanism of the Neuron Sensitization to the Repeated Glutamate Challenge

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Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology Aims and scope

Abstract—

Exposure of cultured neurons to high concentrations of Glu leads to a strong depolarization of mitochondria, which develops synchronously with the secondary rise in the intracellular Ca2+ concentration (delayed calcium deregulation, DCD). In this study, using the primary culture of rat cerebellar neurons, we investigated the mechanism of neuronal sensitization, which manifests itself in the reduction of latent periods of DCD during repeated exposures to Glu. It was shown that the most likely cause of sensitization is the inability of mitochondria to maintain a high transmembrane potential (ΔΨm) as a result of an increase in the proton conductivity of the internal mitochondrial membrane, but not the opening of the mitochondrial permeability transition pore in the inner mitochondrial membrane. Mitochondrial dysfunction reduces the production of ATP, leading to the inability of neurons to quickly restore the concentration of Na+, ATP, and NADH in the intervals between successive Glu administrations. One of the reasons that aggravate the dysfunction of mitochondria and contribute to the sensitization of neurons to the repeated action of Glu is Ca2+ accumulated in the mitochondria during the first glutamate impact.

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ACKNOWLEDGMENTS

The authors thank Prof. H. Imamura who kindly provided plasmid Ateam1.03 encoding ATP sensor. The work was supported by the Russian Foundation for Basic Research (project nos. 16-04-00792 and 16-04-01869) and by the Russian Science Foundation (project no. 17-15-01487).

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Authors and Affiliations

  1. Scientific Center of Children’s Health, 119991, Moscow, Russia

    R. R. Sharipov & A. M. Surin

  2. Institute of General Pathology and Pathophysiology, 125315, Moscow, Russia

    I. A. Krasilnikova, V. G. Pinelis & A. M. Surin

  3. Pirogov Russian National Research Medical University, 117997, Moscow, Russia

    L. R. Gorbacheva & A. M. Surin

  4. Biology Department, Moscow Lomonosov State University, 119991, Moscow, Russia

    L. R. Gorbacheva

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  1. R. R. Sharipov
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Statement on the welfare of animals. Experiments involving animals were carried out in accordance with ethical principles and normative documents recommended by the European Convention on the protection of vertebrate animals used in experiments (Guide for the Care and Use of Laboratory Animals: Eighth Edition, 2010), as well as in compliance with the Regulations of the appropriate laboratory practice as approved by the order no. 199n of 01.04.2016 of the Russian Federation Ministry of Health.

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Sharipov, R.R., Krasilnikova, I.A., Pinelis, V.G. et al. Study of the Mechanism of the Neuron Sensitization to the Repeated Glutamate Challenge. Biochem. Moscow Suppl. Ser. A 12, 369–381 (2018). https://doi.org/10.1134/S1990747818050057

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