PMID- 35513389 OWN - NLM STAT- MEDLINE DCOM- 20220509 LR - 20221212 IS - 2041-4889 (Electronic) VI - 13 IP - 5 DP - 2022 May 5 TI - SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities. PG - 437 LID - 10.1038/s41419-022-04876-9 [doi] LID - 437 AB - 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. CI - (c) 2022. The Author(s). FAU - Zhang, Yanke AU - Zhang Y AD - Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. AD - Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China. FAU - Wu, Junhong AU - Wu J AD - Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. FAU - Yan, Yin AU - Yan Y AD - Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. FAU - Gu, Yixue AU - Gu Y AD - Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. FAU - Ma, Yuanlin AU - Ma Y AD - Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. FAU - Wang, Min AU - Wang M AD - Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China. FAU - Zhang, Hui AU - Zhang H AD - Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. FAU - Tao, Kaiyan AU - Tao K AD - Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. FAU - Lu, Yang AU - Lu Y AD - Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. FAU - Yu, Weihua AU - Yu W AD - Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. AD - Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016, China. FAU - Jing, Wei AU - Jing W AUID- ORCID: 0000-0002-8118-1573 AD - Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. jingweistar@163.com. FAU - Wang, Xuefeng AU - Wang X AUID- ORCID: 0000-0003-1494-0223 AD - Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. xfyp1218@163.com. FAU - Tian, Xin AU - Tian X AUID- ORCID: 0000-0003-1552-8919 AD - Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. xintian@cqmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220505 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Nerve Tissue Proteins) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Sapap3 protein, mouse) SB - IM MH - Animals MH - *Epilepsy/metabolism MH - *Epilepsy, Temporal Lobe/pathology MH - Hippocampus/metabolism MH - Humans MH - Mice MH - Nerve Tissue Proteins/genetics/metabolism MH - Post-Synaptic Density/metabolism/pathology MH - Receptors, N-Methyl-D-Aspartate/genetics/metabolism MH - Seizures/metabolism MH - Synapses/metabolism PMC - PMC9072407 COIS- The authors declare no competing interests. EDAT- 2022/05/06 06:00 MHDA- 2022/05/10 06:00 PMCR- 2022/05/05 CRDT- 2022/05/05 23:15 PHST- 2021/04/06 00:00 [received] PHST- 2022/04/21 00:00 [accepted] PHST- 2022/04/15 00:00 [revised] PHST- 2022/05/05 23:15 [entrez] PHST- 2022/05/06 06:00 [pubmed] PHST- 2022/05/10 06:00 [medline] PHST- 2022/05/05 00:00 [pmc-release] AID - 10.1038/s41419-022-04876-9 [pii] AID - 4876 [pii] AID - 10.1038/s41419-022-04876-9 [doi] PST - epublish SO - Cell Death Dis. 2022 May 5;13(5):437. doi: 10.1038/s41419-022-04876-9.