Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice

Olga C. Jorge-Torres, Karolina Szczesna, Laura Roa, Carme Casal, Louisa Gonzalez-Somermeyer, Marta Soler, Cecilia D. Velasco, Pablo Martinez-San Segundo, Paolo Petazzi, Mauricio A. Saez, Raul Delgado-Morales, Stephane Fourcade, Aurora Pujol, Dori Huertas, Artur Llobet, Sonia Guil*, Manel Esteller*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Web of Science)

Abstract

Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG- binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763.
Original languageEnglish
Pages (from-to)1665-1677
Number of pages13
JournalCell Reports
Volume23
Issue number6
DOIs
Publication statusPublished - 8 May 2018

Keywords

  • GLYCOGEN-SYNTHASE KINASE-3
  • LONG-TERM POTENTIATION
  • ALZHEIMERS-DISEASE
  • MOUSE MODEL
  • TYROSINE PHOSPHORYLATION
  • PROTEIN-SYNTHESIS
  • INACTIVATION
  • MECP2
  • GSK3-BETA
  • NEURONS

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