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      SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities


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          Aberrantly synchronized neuronal discharges in the brain lead to epilepsy, a devastating neurological disease whose pathogenesis and mechanism are unclear. SAPAP3, a cytoskeletal protein expressed at high levels in the postsynaptic density (PSD) of excitatory synapses, has been well studied in the striatum, but the role of SAPAP3 in epilepsy remains elusive. In this study, we sought to investigate the molecular, cellular, electrophysiological and behavioral consequences of SAPAP3 perturbations in the mouse hippocampus. We identified a significant increase in the SAPAP3 levels in patients with temporal lobe epilepsy (TLE) and in mouse models of epilepsy. In addition, behavioral studies showed that the downregulation of SAPAP3 by shRNA decreased the seizure severity and that the overexpression of SAPAP3 by recombinant SAPAP3 yielded the opposite effect. Moreover, SAPAP3 affected action potentials (APs), miniature excitatory postsynaptic currents (mEPSCs) and N-methyl-D-aspartate receptor (NMDAR)-mediated currents in the CA1 region, which indicated that SAPAP3 plays an important role in excitatory synaptic transmission. Additionally, the levels of the GluN2A protein, which is involved in synaptic function, were perturbed in the hippocampal PSD, and this perturbation was accompanied by ultrastructural morphological changes. These results revealed a previously unknown function of SAPAP3 in epileptogenesis and showed that SAPAP3 may represent a novel target for the treatment of epilepsy.

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          Most cited references51

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          Modification of seizure activity by electrical stimulation: II. Motor seizure

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            Variability, compensation and homeostasis in neuron and network function.

            Neurons in most animals live a very long time relative to the half-lives of all of the proteins that govern excitability and synaptic transmission. Consequently, homeostatic mechanisms are necessary to ensure stable neuronal and network function over an animal's lifetime. To understand how these homeostatic mechanisms might function, it is crucial to understand how tightly regulated synaptic and intrinsic properties must be for adequate network performance, and the extent to which compensatory mechanisms allow for multiple solutions to the production of similar behaviour. Here, we use examples from theoretical and experimental studies of invertebrates and vertebrates to explore several issues relevant to understanding the precision of tuning of synaptic and intrinsic currents for the operation of functional neuronal circuits.
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              Heteromeric NMDA receptors: molecular and functional distinction of subtypes.

              The N-methyl D-aspartate (NMDA) receptor subtype of glutamate-gated ion channels possesses high calcium permeability and unique voltage-dependent sensitivity to magnesium and is modulated by glycine. Molecular cloning identified three complementary DNA species of rat brain, encoding NMDA receptor subunits NMDAR2A (NR2A), NR2B, and NR2C, which are 55 to 70% identical in sequence. These are structurally related, with less than 20% sequence identity, to other excitatory amino acid receptor subunits, including the NMDA receptor subunit NMDAR1 (NR1). Upon expression in cultured cells, the new subunits yielded prominent, typical glutamate- and NMDA-activated currents only when they were in heteromeric configurations with NR1. NR1-NR2A and NR1-NR2C channels differed in gating behavior and magnesium sensitivity. Such heteromeric NMDA receptor subtypes may exist in neurons, since NR1 messenger RNA is synthesized throughout the mature rat brain, while NR2 messenger RNA show a differential distribution.

                Author and article information

                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                5 May 2022
                5 May 2022
                May 2022
                : 13
                : 5
                : 437
                [1 ]GRID grid.452206.7, ISNI 0000 0004 1758 417X, Department of Neurology, Chongqing Key Laboratory of Neurology, , The First Affiliated Hospital of Chongqing Medical University, ; 1 Youyi Road, Chongqing, 400016 China
                [2 ]GRID grid.452252.6, ISNI 0000 0004 8342 692X, Department of Neurology, , Affiliated Hospital of Jining Medical University, ; Jining, Shandong China
                [3 ]GRID grid.452206.7, ISNI 0000 0004 1758 417X, Department of Geriatrics, , The First Affiliated Hospital of Chongqing Medical University, ; 1 Youyi Road, Chongqing, 400016 China
                [4 ]GRID grid.203458.8, ISNI 0000 0000 8653 0555, Institute of Neuroscience, Chongqing Medical University, ; Chongqing, 400016 China
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                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                : 6 April 2021
                : 15 April 2022
                : 21 April 2022
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81901324
                Award ID: 81671286
                Award ID: 81871019
                Award ID: 82001378
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                © The Author(s) 2022

                Cell biology
                diagnostic markers,epilepsy
                Cell biology
                diagnostic markers, epilepsy


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