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Stem Cell Reports. 2018 Dec 11;11(6):1449-1461. doi: 10.1016/j.stemcr.2018.11.003. Epub 2018 Nov 29.

Increased Calcium Influx through L-type Calcium Channels in Human and Mouse Neural Progenitors Lacking Fragile X Mental Retardation Protein.

Author information

1
Faculty of Medicine, Physiology, University of Helsinki, PO Box 63, FIN-00014 University of Helsinki, Helsinki, Finland.
2
Array and Analysis Facility, Department of Medical Sciences, Uppsala University, PO Box 3056, 75003 Uppsala, Sweden.
3
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan.
4
Faculty of Medicine, Physiology, University of Helsinki, PO Box 63, FIN-00014 University of Helsinki, Helsinki, Finland. Electronic address: maija.castren@helsinki.fi.

Abstract

The absence of FMR1 protein (FMRP) causes fragile X syndrome (FXS) and disturbed FMRP function is implicated in several forms of human psychopathology. We show that intracellular calcium responses to depolarization are augmented in neural progenitors derived from human induced pluripotent stem cells and mouse brain with FXS. Increased calcium influx via nifedipine-sensitive voltage-gated calcium (Cav) channels contributes to the exaggerated responses to depolarization and type 1 metabotropic glutamate receptor activation. The ratio of L-type/T-type Cav channel expression is increased in FXS progenitors and correlates with enhanced progenitor differentiation to glutamate-responsive cells. Genetic reduction of brain-derived neurotrophic factor in FXS mouse progenitors diminishes the expression of Cav channels and activity-dependent responses, which are associated with increased phosphorylation of the phospholipase C-γ1 site within TrkB receptors and changes of differentiating progenitor subpopulations. Our results show developmental effects of increased calcium influx via L-type Cav channels in FXS neural progenitors.

KEYWORDS:

BDNF; fragile X syndrome; glutamate receptors; intracellular calcium; neural progenitors; voltage-gated calcium channels

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