FMR1 loss in a human stem cell model reveals early changes to intrinsic membrane excitability.

FMR1 loss in a human stem cell model reveals early changes to intrinsic membrane excitability. Dev Biol. 2020 Sep 22;: Authors: Susco SG, Arias-García MA, López-Huerta VG, Beccard A, Bara AM, Moffitt J, Korn J, Fu Z, Barrett LE Abstract Fragile X mental retardation 1 (FMR1) encodes the RNA binding protein FMRP. Loss of FMRP drives Fragile X syndrome (FXS), the leading inherited cause of intellectual disability and a leading monogenic cause of autism. While cortical hyperexcitability is a hallmark of FXS, the reported phenotypes and underlying mechanisms, including alterations in synaptic transmission and ion channel properties, are heterogeneous and at times contradictory. Here, we report the generation of new isogenic FMR1y/+ and FMR1y/- human pluripotent stem cell (hPSC) lines using CRISPR-Cas9 to facilitate the study of how complete FMRP loss, independent of genetic background, drives molecular and cellular alterations relevant for FXS. After differentiating these stem cell tools into excitatory neurons, we systematically assessed the impact of FMRP loss on intrinsic membrane and synaptic properties over time. Using whole-cell patch clamp analyses, we found that FMR1y/- neurons overall showed an increased intrinsic membrane excitability compared to age-matched FMR1y/+ controls, with no discernable alternations in synaptic transmission. Surprisingly, longitudinal analyses of cell intrinsic defects revealed that a majority of sign...
Source: Developmental Biology - Category: Biology Authors: Tags: Dev Biol Source Type: research