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

Summary 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.
Highlights • Responses to activity are augmented in neural progenitors in fragile X syndrome (FXS). • Increased Ca2+ influx contributes to the exaggerated FXS progenitor responses • L-type voltage-gated channels are abnormally activated in FXS progenitors • Reduced BDNF diminishes Ca2+ influx and modulates FXS progenitor differentiation
In this article, Maija Castrén and colleagues show contribution of increased Ca2+ influx through L-type voltage-gated calcium channels to augmented responses to depolarization and glutamate receptor activation in neural progenitors derived from human induced pluripotent stem cells (iPSCs) and mouse brain modeling fragile X syndrome.