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      Alterations in Properties of Glutamatergic Transmission in the Temporal Cortex and Hippocampus Following Pilocarpine-Induced Acute Seizures in Wistar Rats

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          Abstract

          Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy in humans, and is often developed after an initial precipitating brain injury. This form of epilepsy is frequently resistant to pharmacological treatment; therefore, the prevention of TLE is the prospective approach to TLE therapy. The lithium-pilocarpine model in rats replicates some of the main features of TLE in human, including the pathogenic mechanisms of cell damage and epileptogenesis after a primary brain injury. In the present study, we investigated changes in the properties of glutamatergic transmission during the first 3 days after pilocarpine-induced acute seizures in Wistar rats (PILO-rats). Using RT-PCR and electrophysiological techniques, we compared the changes in the temporal cortex (TC) and hippocampus, brain areas differentially affected by seizures. On the first day, we found a transient increase in a ratio of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl d-aspartate (NMDA) receptors in the excitatory synaptic response in pyramidal neurons of the CA1 area of the dorsal hippocampus, but not in the TC. This was accompanied by an increase in the slope of input-output (I/O) curves for fEPSPs recorded in CA1, suggesting an enhanced excitability in AMPARs in this brain area. There was no difference in the AMPA/NMDA ratio in control rats on the third day. We also revealed the alterations in NMDA receptor subunit composition in PILO-rats. The GluN2B/GluN2A mRNA expression ratio increased in the dorsal hippocampus but did not change in the ventral hippocampus or the TC. The kinetics of NMDA-mediated evoked EPSCs in hippocampal neurons was slower in PILO-rats compared with control animals. Ifenprodil, a selective antagonist of GluN2B-containing NMDARs, diminished the area and amplitude of evoked EPSCs in CA1 pyramidal cells more efficiently in PILO-rats compared with control animals. These results demonstrate that PILO-induced seizures lead to more severe alterations in excitatory synaptic transmission in the dorsal hippocampus than in the TC. Seizures affect the relative contribution of AMPA and NMDA receptor conductances in the synaptic response and increase the proportion of GluN2B-containing NMDARs in CA1 pyramidal neurons. These alterations disturb normal circuitry functions in the hippocampus, may cause neuron damage, and may be one of the important pathogenic mechanisms of TLE.

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          Most cited references 72

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          The pilocarpine model of temporal lobe epilepsy

          Understanding the pathophysiogenesis of temporal lobe epilepsy (TLE) largely rests on the use of models of status epilepticus (SE), as in the case of the pilocarpine model. The main features of TLE are: (i) epileptic foci in the limbic system; (ii) an “initial precipitating injury”; (iii) the so-called “latent period”; and (iv) the presence of hippocampal sclerosis leading to reorganization of neuronal networks. Many of these characteristics can be reproduced in rodents by systemic injection of pilocarpine; in this animal model, SE is followed by a latent period and later by the appearance of spontaneous recurrent seizures (SRSs). These processes are, however, influenced by experimental conditions such as rodent species, strain, gender, age, doses and routes of pilocarpine administration, as well as combinations with other drugs administered before and/or after SE. In the attempt to limit these sources of variability, we evaluated the methodological procedures used by several investigators in the pilocarpine model; in particular, we have focused on the behavioural, electrophysiological and histopathological findings obtained with different protocols. We addressed the various experimental approaches published to date, by comparing mortality rates, onset of SRSs, neuronal damage, and network reorganization. Based on the evidence reviewed here, we propose that the pilocarpine model can be a valuable tool to investigate the mechanisms involved in TLE, and even more so when standardized to reduce mortality at the time of pilocarpine injection, differences in latent period duration, variability in the lesion extent, and SRS frequency.
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            Receptor trafficking and synaptic plasticity.

            Long-term potentiation and long-term depression are processes that have been widely studied to understand the molecular basis of information storage in the brain. Glutamate receptors are required for the induction and expression of these forms of plasticity, and GABA (gamma-aminobutyric acid) receptors are involved in their modulation. Recent insights into how these receptors are rapidly moved into and out of synaptic membranes has profound implications for our understanding of the mechanisms of long-term potentiation and long-term depression.
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              Transient incorporation of native GluR2-lacking AMPA receptors during hippocampal long-term potentiation.

              Postnatal glutamatergic principal neuron synapses are typically presumed to express only calcium-impermeable (CI), GluR2-containing AMPARs under physiological conditions. Here, however, we demonstrate that long-term potentiation (LTP) in CA1 hippocampal pyramidal neurons causes rapid incorporation of GluR2-lacking calcium-permeable (CP)-AMPARs: CP-AMPARs are present transiently, being replaced by GluR2-containing AMPARs approximately 25 min after LTP induction. Thus, CP-AMPARs are physiologically expressed at CA1 pyramidal cell synapses during LTP, and may be required for LTP consolidation.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                31 August 2017
                2017
                : 11
                Affiliations
                1Laboratory of Molecular Mechanisms of Neural Interactions, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences Saint Petersburg, Russia
                2Federal Almazov North-West Medical Research Centre, Institute of Experimental Medicine Saint Petersburg, Russia
                Author notes

                Edited by: Andrea Nistri, Scuola Internazionale di Studi Superiori Avanzati (SISSA), Italy

                Reviewed by: Renato Corradetti, University of Florence, Italy; Maxime Lévesque, McGill University, Canada

                *Correspondence: Aleksey V. Zaitsev aleksey_zaitsev@ 123456mail.ru

                †Present Address: Ekaterina A. Veniaminova, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

                Article
                10.3389/fncel.2017.00264
                5584016
                Copyright © 2017 Amakhin, Malkin, Ergina, Kryukov, Veniaminova, Zubareva and Zaitsev.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 7, Tables: 1, Equations: 12, References: 79, Pages: 16, Words: 10114
                Funding
                Funded by: Russian Science Foundation 10.13039/501100006769
                Award ID: 16-15-10202
                Categories
                Neuroscience
                Original Research

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