Dubna, Moscow, Russian Federation
Dubna, Moscow, Russian Federation
Dubna, Moscow, Russian Federation
Dubna, Moscow, Russian Federation
In this paper, we have proposed a model approach for analyzing the properties of hippocampal neural networks with different types of NMDA receptors: GluN1/GluN2A, GluN1/GluN2B, GluN1/GluN2A/GluN2B. Molecular dynamics modeling of the activation of the ion channel of NMDA receptors modified by the action of allosteric modulators was carried out. The study of the network activity of neurons with a modified structure of NMDA receptors was carried out in models of neural networks in the CA1 and CA3 regions of the hippocampus. As a result of studying the properties of the neural network of the hippocampus with a modified structure of NMDA receptors, the electrophysiological characteristics of the neural network model were obtained depending on the structure of the ion channel of the NMDA receptor. Based on the analysis of changes in the conductivities of the ion channel and the binding of magnesium ions, differences in the amplitude of the theta and gamma frequency ranges in neural networks with different model structures of NMDA receptors were revealed. Analysis of the network activity of neurons with different types of NMDA revealed minor changes in the ion channel conductance and local potential depending on the subunits that make up the receptor and the type of modulator. Under the influence of Ro 25-6981 and ketamine for the diheteromeric model of the GluN1/GluN2A NMDA receptor, a decrease in the amplitude of the theta-frequency ranges and an increase in the gamma-frequency ranges were observed in comparison with the native forms of the receptor. For the GluN1/GluN2A/GluN2B trigger heteromer, there is an increase in theta frequency and a decrease in the gamma frequency compared to GluN1/GluN2B. In the absence of ketamine, for the GluN1/GluN2A and GluN1/GluN2A/GluN2B NMDA receptor models, an increase in the amplitude of theta-frequency and gamma-frequency ranges was observed compared to the native forms of the NMDA receptor.
hippocampus, NMDA receptor, Alzheimer’s disease, molecular dynamics, neural network
1. Vyklicky V., Korinek M., Smejkalova T., Balik A., Krausova B., Kaniakova M., Lichnerova K., Cerny J., Krusek J., Dittert I., Horak M., Vyklicky L. Structure, function, and pharmacology of NMDA receptor channels. Physiol. Res, 2014, vol. 63, suppl. 1, pp. S191-203, doi:https://doi.org/10.33549/physiolres.932678.
2. Wang C.C. et al. A critical role for GluN2B-containing NMDA receptors in cortical development and function. Neuron, 2011, vol. 72, pp. 789-805, doi:https://doi.org/10.1016/j.neuron.2011.09.023.
3. Kumar A. NMDA Receptor Function During Senescence: Implication on Cognitive Performance. Front. Neurosci., 2015, doi:https://doi.org/10.3389/fnins.2015.00473.
4. Blanke M.L., VanDongen A.M.J. Activation Mechanisms of the NMDA Receptor. Biology of the NMDA Receptor. CRC Press, 2009, chapter 13.
5. Myers J.S., Yuan H., Kang J.-Q., Tan F.Ch.K. Distinct roles of GRIN2A and GRIN2B variants in neurological conditions. F1000Res., 2019, vol. 8, doi:https://doi.org/10.12688/f1000research.18949.1.
6. Wang H. et al. Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors. Neuron, 2021, vol. 109, pp. 2443-2456, doi:https://doi.org/10.1016/j.neuron.2021.05.031.
7. Monaghan D.T. et al. Pharmacological Modulation of NMDA Receptor Activity and the Advent of Negative and Positive Allosteric Modulators. Neurochem. Int., 2012, vol. 61, no. 4, pp. 581-592, doi:https://doi.org/10.1016/j.neuint.2012.01.004.
8. Neymotin S.A. et al. Ketamine disrupts theta modulation of gamma in a computer model of hippocampus. J. Neurosci., 2011, vol. 31, pp. 11733-11743, doi:https://doi.org/10.1523/JNEUROSCI.0501-11.2011.
9. Saudargiene A., Cobb S., Graham B.P. A computational study on plasticity during theta cycles at Schaffer collateral synapses on CA1 pyramidal cells in the hippocampus. Hippocampus, 2015, vol. 25, no. 2, pp. 208-218, doi:https://doi.org/10.1002/hipo.22365.
10. Cutsuridis V., Cobb S., Graham B.P. Encoding and Retrieval in a Model of the Hippocampal CA1 Microcircuit. Hippocampus, 2010, vol. 20, pp. 423-446, doi:https://doi.org/10.1002/hipo.20661.
11. Hines M.L., Carnevale N.T. The NEURON simulation environment. Neural Comput., 1997, vol. 9, pp. 1179-1209, doi:https://doi.org/10.1162/neco.1997.9.6.1179.
12. Hong L.E. at al. Gamma and delta neural oscillations and association with clinical symptoms under subanesthetic ketamine. Neuropsychopharmacology, 2010, vol. 35, pp. 632-640.
13. Smart O.S., Neduvelil J.G., Wang X., Wallace B.A., Sansom M.S. HOLE: A program for the analysis of the pore dimensions of ion channel structural models. J. Molec. Graphics, 1996, vol. 14, pp. 354-360, doi:https://doi.org/10.1016/S0263-7855(97)00009-X.
14. Aksenova S.V., Batova A.S., Bugay A.N., Dushanov E.B. Modeling of the main rhythms of the hippocampus with different types of NMDA receptors. Russian Journal of Biological Physics and Chemistry, 2021, vol. 6, no. 2, pp. 55-56. (In Russ.)
15. Batova A.S., Bugay A.N., Dushanov E.B. Effect of mutant NMDA receptors on oscillations in a model of Hippocampus. Journal of Bioinformatics and Computational Biology, 2019, vol. 17, no. 01, doi:https://doi.org/10.1142/S0219720019400031.
