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The Fragile X Syndrome – Where Do We Go?

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00342

New insights into the role of Cav2 protein family in calcium flux deregulation in Fmr1-KO neurons.

 Sara Castagnola1, 2, 3, Sébastien Delhaye1, 2, 3,  Alessandra Folci1, 2,  Fabrice Duprat2,  Marielle Jarjat1, 2, 3, Mauro Grossi1, 2, 3,  Méline Béal1, 2, 3,  Stéphane MARTIN2,  Massimo Mantegazza2,  Barbara Bardoni2, 3 and  Thomas Maurin1, 2, 3*
  • 1CNRS, IPMC, Université Côte d'Azur, France
  • 2INSERM, CNRS, IPMC, Université Côte d'Azur, France
  • 3LIA “Neogenex”, Centre national de la recherche scientifique (CNRS), France

Fragile X syndrome (FXS), the most common form of inherited intellectual disability and a leading cause of autism, results from the loss of expression of the Fmr1 gene which encodes the RNA-binding protein FMRP (Fragile X Mental Retardation Protein). Among the thousands mRNA targets of FMRP, numerous encode regulators of ion homeostasis. It has also been described that FMRP directly interacts with Ca2+ channels modulating their activity. Collectively these findings suggest that FMRP plays critical roles in Ca2+ homeostasis during nervous system development. We carried out a functional analysis of Ca2+ regulation using a calcium imaging approach in Fmr1-KO cultured neurons and we show that these cells display impaired steady state Ca2+ concentration and an altered entry of Ca2+ after KCl-triggered depolarization. Consistent with these data, we show that the protein product of the Cacna1a gene, the pore-forming subunit of the Cav2.1 channel, is less expressed at the plasma membrane of Fmr1-KO neurons compared to WT. Thus, our findings point out the critical role that Cav2.1 plays in the altered Ca2+ flux in Fmr1-KO neurons, impacting Ca2+ homeostasis of these cells. Remarkably, we highlight a new phenotype of cultured Fmr1-KO neurons that can be considered a novel cellular biomarker and is amenable to small molecule screening and identification of new drugs to treat FXS.

Keywords: Fragile X Syndrome, CaV2.1, calcium homeostasis, ratiometric calcium imaging, CACNA1A

Received: 16 Apr 2018; Accepted: 30 Aug 2018.

Edited by:

Regina Dahlhaus, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany

Reviewed by:

Christina Gross, Cincinnati Children's Hospital Medical Center, United States
Maija L. Castrén, University of Helsinki, Finland  

Copyright: © 2018 Castagnola, Delhaye, Folci, Duprat, Jarjat, Grossi, Béal, MARTIN, Mantegazza, Bardoni and Maurin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Thomas Maurin, Université Côte d'Azur, CNRS, IPMC, Nice, 06560, France,