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SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities
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 s...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9072407/ https://www.ncbi.nlm.nih.gov/pubmed/35513389 http://dx.doi.org/10.1038/s41419-022-04876-9 |
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author | Zhang, Yanke Wu, Junhong Yan, Yin Gu, Yixue Ma, Yuanlin Wang, Min Zhang, Hui Tao, Kaiyan Lü, Yang Yu, Weihua Jing, Wei Wang, Xuefeng Tian, Xin |
author_facet | Zhang, Yanke Wu, Junhong Yan, Yin Gu, Yixue Ma, Yuanlin Wang, Min Zhang, Hui Tao, Kaiyan Lü, Yang Yu, Weihua Jing, Wei Wang, Xuefeng Tian, Xin |
author_sort | Zhang, Yanke |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9072407 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90724072022-05-07 SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities Zhang, Yanke Wu, Junhong Yan, Yin Gu, Yixue Ma, Yuanlin Wang, Min Zhang, Hui Tao, Kaiyan Lü, Yang Yu, Weihua Jing, Wei Wang, Xuefeng Tian, Xin Cell Death Dis Article 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. Nature Publishing Group UK 2022-05-05 /pmc/articles/PMC9072407/ /pubmed/35513389 http://dx.doi.org/10.1038/s41419-022-04876-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zhang, Yanke Wu, Junhong Yan, Yin Gu, Yixue Ma, Yuanlin Wang, Min Zhang, Hui Tao, Kaiyan Lü, Yang Yu, Weihua Jing, Wei Wang, Xuefeng Tian, Xin SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities |
title | SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities |
title_full | SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities |
title_fullStr | SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities |
title_full_unstemmed | SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities |
title_short | SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities |
title_sort | sapap3 regulates epileptic seizures involving glun2a in post-synaptic densities |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9072407/ https://www.ncbi.nlm.nih.gov/pubmed/35513389 http://dx.doi.org/10.1038/s41419-022-04876-9 |
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