CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility

被引：90

作者：

Okuda, Kosuke ^{[1
]}

Kobayashi, Shizuka ^{[2
]}

Fukaya, Masahiro ^{[3
]}

Watanabe, Aya ^{[1
]}

Murakami, Takuto ^{[1
]}

Hagiwara, Mai ^{[1
]}

Sato, Tempei ^{[4
]}

Ueno, Hiroe ^{[4
]}

Ogonuki, Narumi ^{[5
]}

Komano-Inoue, Sayaka ^{[6
]}

Manabe, Hiroyuki ^{[6
]}

Yamaguchi, Masahiro ^{[6
]}

Ogura, Atsuo ^{[5
]}

Asahara, Hiroshi ^{[4
,7
,8
]}

Sakagami, Hiroyuki ^{[3
]}

Mizuguchi, Masashi ^{[1
]}

Manabe, Toshiya ^{[2
]}

Tanaka, Teruyuki ^{[1
]}

机构：

[1] Univ Tokyo, Grad Sch Med, Dept Dev Med Sci, Tokyo 1130033, Japan

[2] Univ Tokyo, Inst Med Sci, Div Neuronal Network, Tokyo 1088639, Japan

[3] Kitasato Univ, Sch Med, Dept Anat, Sagamihara, Kanagawa 2520374, Japan

[4] Natl Res Inst Child Hlth & Dev, Dept Syst Biomed, Tokyo 1578535, Japan

[5] RIKEN BioResource Ctr, Bioresource Engn Div, Tsukuba, Ibaraki 3050074, Japan

[6] Univ Tokyo, Grad Sch Med, Dept Physiol, Tokyo 1130033, Japan

[7] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA

[8] Tokyo Med & Dent Univ, Dept Syst BioMed, Tokyo 1138510, Japan

来源：

NEUROBIOLOGY OF DISEASE | 2017年 / 106卷

基金：

日本学术振兴会;

关键词：

CDKL5; Developmental disorders; Epilepsy; Hippocampus; Excitatory synapses; NMDA receptors; GluN2B; SAP102; Ifenprodil; DEPENDENT PHOSPHORYLATION; RETT-SYNDROME; MOUSE MODEL; PROTEIN; NR2B; TRAFFICKING; SUBUNITS; GENE; ENCEPHALOPATHIES; IDENTIFICATION;

D O I：

10.1016/j.nbd.2017.07.002

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Mutations in the Cyclin-dependent kinase-like 5 (CMS) gene cause severe neurodevelopmental disorders accompanied by intractable epilepsies, i.e. West syndrome or atypical Rett syndrome. Here we report generation of the Cdkl5 knockout mouse and show that CDKL5 controls postsynaptic localization of GIuN2B-containing Nmethyl-n-aspartate (NMDA) receptors in the hippocampus and regulates seizure susceptibility. Cdkl5 -/Y mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA. In concordance with this result, electrophysiological analysis in the hippocampal CAl region disclosed an increased ratio of NMDA/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) and a significantly larger decay time constant of NMDA receptor-mediated EPSCs (NMDA-EPSCs) as well as a stronger inhibition of the NMDA-EPSCs by the GIuN2B-selective antagonist ifenprodil in Cdkl5 -/Y mice. Subcellular fractionation of the hippocampus from Cdkl5 -/Y mice revealed a significant increase of GIuN2B and SAP102 in the PSD (postsynaptic density)-1T fraction, without changes in the S1 (post-nuclear) fraction or mRNA transcripts, indicating an intracellular distribution shift of these proteins to the PSD. Immunoelectron microscopic analysis of the hippocampal CAl region further confirmed postsynaptic overaccumulation of GIuN2B and SAP102 in CdkIS -/Y mice. Furthermore, ifenprodil abrogated the NMDA-induced hyperexcitability in Cdkl5 -/Y mice, suggesting that upregulation of GIuN2B accounts for the enhanced seizure susceptibility. These data indicate that CDKL5 plays an important role in controlling postsynaptic localization of the GIuN2B-SAP102 complex in the hippocampus and thereby regulates seizure susceptibility, and that aberrant NMDA receptor-mediated synaptic transmission underlies the pathological mechanisms of the CDKL5 loss-of-function. (C) 2017 Elsevier Inc. All rights reserved.

引用

页码：158 / 170

页数：13

共 64 条

[1]

Acsády L, 1998, J NEUROSCI, V18, P3386

[2] Mapping Pathological Phenotypes in a Mouse Model of CDKL5 Disorder [J].

Amendola, Elena ;

Zhan, Yang ;

Mattucci, Camilla ;

Castroflorio, Enrico ;

Calcagno, Eleonora ;

Fuchs, Claudia ;

Lonetti, Giuseppina ;

Silingardi, Davide ;

Vyssotski, Alexei L. ;

Farley, Dominika ;

Ciani, Elisabetta ;

Pizzorusso, Tommaso ;

Giustetto, Maurizio ;

Gross, Cornelius T. .

PLOS ONE, 2014, 9 (05)

[3] CDKL5-Related Disorders: From Clinical Description to Molecular Genetics [J].

Bahi-Buisson, N. ;

Bienvenu, T. .

MOLECULAR SYNDROMOLOGY, 2011, 2 (3-5) :137-152

[4] Key clinical features to identify girls with CDKL5 mutations [J].

Bahi-Buisson, Nadia ;

Nectoux, Juliette ;

Rosas-Vargas, Haydee ;

Milh, Mathieu ;

Boddaert, Nathalie ;

Girard, Benoit ;

Cances, Claude ;

Ville, Dorothee ;

Afenjar, Alexandra ;

Rio, Marlene ;

Heron, Delphine ;

Morel, Marie Ange N'Guyen ;

Arzimanoglou, Alexis ;

Philippe, Christophe ;

Jonveaux, Philippe ;

Chelly, Jamel ;

Bienvenu, Thierry .

BRAIN, 2008, 131 :2647-2661

[5] Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation [J].

Bertani, Ilaria ;

Rusconi, Laura ;

Bolognese, Fabrizio ;

Forlani, Greta ;

Conca, Barbara ;

De Monte, Lucia ;

Badaracco, Gianfranco ;

Landsberger, Nicoletta ;

Kilstrup-Nielsen, Charlotte .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (42) :32048-32056

[6] Timing and efficacy of transmitter release at mossy fiber synapses in the hippocampal network [J].

Bischofberger, Josef ;

Engel, Dominique ;

Frotscher, Michael ;

Jonas, Peter .

PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 2006, 453 (03) :361-372

[7] The neuropeptide nociceptin is a synaptically released endogenous inhibitor of hippocampal long-term potentiation [J].

Bongsebandhu-phubhakdi, Saknan ;

Manabe, Toshiya .

JOURNAL OF NEUROSCIENCE, 2007, 27 (18) :4850-4858

[8] CDKL5 is a brain MeCP2 target gene regulated by DNA methylation [J].

Carouge, Delphine ;

Host, Lionel ;

Aunis, Dominique ;

Zwiller, Jean ;

Anglard, Patrick .

NEUROBIOLOGY OF DISEASE, 2010, 38 (03) :414-424

[9] 2B or Not 2B: A Tail of Two NMDA Receptor Subunits [J].

Cepeda, Carlos ;

Levine, Michael S. .

NEURON, 2012, 74 (03) :426-428

[10] NMDA Receptor-Dependent Regulation of Dendritic Spine Morphology by SAP102 Splice Variants [J].

Chen, Bo-Shiun ;

Thomas, Eleanor V. ;

Sanz-Clemente, Antonio ;

Roche, Katherine W. .

JOURNAL OF NEUROSCIENCE, 2011, 31 (01) :89-96

← 1 2 3 4 5 6 7 →