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

Okuda, Kosuke; Kobayashi, Shizuka; Fukaya, Masahiro; Watanabe, Aya; Murakami, Takuto; Hagiwara, Mai; Sato, Tempei; Ueno, Hideto; Ogonuki, Narumi; Komano-Inoue, Sayaka; Manabe, Hiroyuki; Yamaguchi, Masahiro; Ogura, Atsuo; Asahara, Hiroshi; Sakagami, Hiroyuki; Mizuguchi, Masashi; Manabe, Toshiya; Tanaka, Teruyuki

doi:10.1016/j.nbd.2017.07.002

Cited by 99 publications

(147 citation statements)

References 64 publications

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“…In this light, the NMDA receptor‐mediated synaptic response is enhanced in the hippocampus of Cdkl5 knockout mice, and the N2B subunit of the NMDA receptor over‐accumulates in post‐synaptic densities of hippocampal neurons in these mice (Okuda et al , ). Furthermore, the enhanced seizure susceptibility seen in Cdkl5 knockout mice is abrogated by an NMDA receptor antagonist (Okuda et al , ). Intriguingly, Ser 900 in MAP1S lies close to one of two reported microtubule‐binding domains (Orban‐Nemeth et al , ; Ding et al , ; Dallol et al , ).…”

Section: Discussionmentioning

confidence: 85%

Phosphoproteomic screening identifies physiological substrates of the CDKL 5 kinase

et al. 2018

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Mutations in the gene encoding the protein kinase CDKL5 cause a debilitating neurodevelopmental disease termed CDKL5 disorder. The impact of these mutations on CDKL5 function is poorly understood because the substrates and cellular processes controlled by CDKL5 are unclear. Here, we describe a quantitative phosphoproteomic screening which identified MAP1S, CEP131 and DLG5—regulators of microtubule and centrosome function—as cellular substrates of CDKL5. Antibodies against MAP1S phospho‐Ser900 and CEP131 phospho‐Ser35 confirmed CDKL5‐dependent phosphorylation of these targets in human cells. The phospho‐acceptor serine residues in MAP1S, CEP131 and DLG5 lie in the motif RPXSA, although CDKL5 can tolerate residues other than Ala immediately C‐terminal to the phospho‐acceptor serine. We provide insight into the control of CDKL5 activity and show that pathogenic mutations in CDKL5 cause a major reduction in CDKL5 activity in vitro and in cells. These data reveal the first cellular substrates of CDKL5, which may represent important biomarkers in the diagnosis and treatment of CDKL5 disorder, and illuminate the functions of this poorly characterized kinase.

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Section: Discussionmentioning

confidence: 85%

Phosphoproteomic screening identifies physiological substrates of the CDKL 5 kinase

et al. 2018

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“…The CDKL5 variants reported in these cases were considered either pathogenic or likely pathogenic. Interestingly, seizures have been noticeably absent from the phenotype of mouse models with three lines of CDKL5 knockout mice being generated without any features of epilepsy (Amendola et al, ; Okuda et al, ; Wang et al, ).…”

Section: Discussionmentioning

confidence: 99%

Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory?

MacKay

Bick

Prokop

et al. 2020

American J of Med Genetics Pt A

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Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene cause the neurodevelopmental disorder, the CDKL5 deficiency disorder. Reports of individuals with pathogenic variants in CDKL5 without seizures are exceedingly rare, and indepth analyses of their variants have been lacking. Whole-genome sequencing was performed on a 29-year-old female with mild intellectual disability who, in the absence of overt seizures, presented with multiple episodes of altered mental status over a 24-year period. Clinical history was supplemented by a parent completed questionnaire from the International CDKL5 Disorder Database. We identified a de novo heterozygous variant in CDKL5 (NM_003159.2:c.645T>A;p.Ser215Arg). Indepth computational analysis performed to predict the impact of the variant on protein structure and function demonstrated that the variant was likely pathogenic. In this light, cell-based studies showed that the S215R substitution causes a marked reduction in CDKL5 kinase activity. Similarities between our case and one previously reported case are striking. These cases, both without seizures but with apparent behavioral symptomatology, together question whether seizures are mandatory in this neurodevelopmental disorder. K E Y W O R D S

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“…Cyclin‐dependent kinase like 5 (CDKL5) encephalopathy consists of infantile spasms in the middle of the first year of life, often preceded by tonic and/or clonic seizures . Cdkl5 knockout mice display significant GluN2B subunit increase in early postnatal life …”

Section: Gene Dysfunction In Age‐dependent Epilepsy Phenotypesmentioning

confidence: 99%

“…16 Cdkl5 knockout mice display significant GluN2B subunit increase in early postnatal life. 17 Dynamin-1 (DNM1) encephalopathy comprises various types of generalized seizures preceded by profound psychomotor impairment. Infantile spasms with hypsarrhythmia or multifocal spikes begin at a median age of 7.5 months and may be followed by Lennox-Gastaut syndrome.…”

Section: Infantile Spasms or West Syndromementioning

confidence: 99%

Gene mutations in paediatric epilepsies cause NMDA‐pathy, and phasic and tonic GABA‐pathy

Gataullina

Bienvenu

Nabbout

et al. 2019

Develop Med Child Neuro

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The aim of this study was to disentangle mechanisms of epileptogenesis in monogenic epilepsies in children. We reviewed paediatric monogenic epilepsies excluding brain malformation or an inborn error of metabolism, but including the gene function whether there is loss‐of‐function or gain‐of‐function, age at gene expression when available, and associated epilepsy syndrome. Genes for which at least five patients with similar epilepsy phenotype had been reported were selected. Three mechanisms are shared by most monogenic epilepsies: (1) excess of N‐methyl‐d‐aspartate (NMDA) transmission activation (NMDA‐pathies); (2) abnormal gamma‐aminobutyric acid (GABA) transmission with reduced inhibition (phasic GABA‐pathies); and (3) tonic activation of extrasynaptic GABAA receptors by extracellular GABA (tonic GABA‐pathies). NMDA‐pathies comprise early epileptic encephalopathy with suppression‐burst, neonatal/infantile benign seizures, West and Lennox–Gastaut syndromes, and encephalopathy with continuous spike waves in slow sleep, thus brief seizures with major interictal spiking. Phasic GABA‐pathies comprise mostly generalized epilepsy with febrile seizures plus and Dravet syndrome, thus long‐lasting seizures with mild interictal spiking. Tonic GABA‐pathies cause epilepsy with myoclonic–atonic seizures and Angelman syndrome, thus major high‐amplitude slow‐wave activity. This pathophysiological approach to monogenic epilepsies provides diagnostic clues and helps to guide treatment strategy. What this paper adds In paediatric monogenic epilepsies, electroclinical patterns point to three main mechanisms: NMDA‐pathies, and phasic and tonic GABA‐pathies. Antiepileptic treatment choice could be guided by each of these mechanisms.

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

Cited by 99 publications

References 64 publications

Phosphoproteomic screening identifies physiological substrates of the CDKL 5 kinase

Phosphoproteomic screening identifies physiological substrates of the CDKL 5 kinase

Expanding the phenotype of the CDKL5 deficiency disorder: Are seizures mandatory?

Gene mutations in paediatric epilepsies cause NMDA‐pathy, and phasic and tonic GABA‐pathy

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