New Insights Into the Role of Cav2 Protein Family in Calcium Flux Deregulation in Fmr1-KO Neurons

Abstract

Fragile X syndrome (FXS), the most common form of inherited intellectual disability (ID) and a leading cause of autism, results from the loss of expression of the <i>Fmr1</i> gene which encodes the RNA-binding protein Fragile X Mental Retardation Protein (FMRP). 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 <i>Fmr1</i>-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 <i>Cacna1a</i> gene, the pore-forming subunit of the Ca_v2.1 channel, is less expressed at the plasma membrane of <i>Fmr1</i>-KO neurons compared to wild-type (WT). Thus, our findings point out the critical role that Ca_v2.1 plays in the altered Ca²⁺ flux in <i>Fmr1</i>-KO neurons, impacting Ca²⁺ homeostasis of these cells. Remarkably, we highlight a new phenotype of cultured <i>Fmr1</i>-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.