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Functional Deficiencies in Fragile X Neurons Derived from Human Embryonic Stem Cells.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2015 Nov 18; Vol. 35 (46), pp. 15295-306. - Publication Year :
- 2015
-
Abstract
- Fragile X syndrome (FXS), the most common form of inherited mental retardation, is a neurodevelopmental disorder caused by silencing of the FMR1 gene, which in FXS becomes inactivated during human embryonic development. We have shown recently that this process is recapitulated by in vitro neural differentiation of FX human embryonic stem cells (FX-hESCs), derived from FXS blastocysts. In the present study, we analyzed morphological and functional properties of neurons generated from FX-hESCs. Human FX neurons can fire single action potentials (APs) to depolarizing current commands, but are unable to discharge trains of APs. Their APs are of a reduced amplitudes and longer durations than controls. These are reflected in reduced inward Na(+) and outward K(+) currents. In addition, human FX neurons contain fewer synaptic vesicles and lack spontaneous synaptic activity. Notably, synaptic activity in these neurons can be restored by coculturing them with normal rat hippocampal neurons, demonstrating a critical role for synaptic mechanisms in FXS pathology. This is the first extensive functional analysis of human FX neurons derived in vitro from hESCs that provides a convenient tool for studying molecular mechanisms underlying the impaired neuronal functions in FXS.<br />Significance Statement: Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by silencing of the FMR1 gene. In this study, we describe for the first time the properties of neurons developed from human embryonic stem cells (hESCs) that carry the FMR1 mutation and are grown in culture for extended periods. These neurons are retarded compared with controls in several morphological and functional properties. In vitro neural differentiation of FX hESCs can thus serve as a most relevant system for the analysis of molecular mechanisms underlying the impaired neuronal functions in FXS.<br /> (Copyright © 2015 the authors 0270-6474/15/3515295-12$15.00/0.)
- Subjects :
- Action Potentials genetics
Animals
Cell Differentiation genetics
Cells, Cultured
Coculture Techniques
Excitatory Postsynaptic Potentials drug effects
Excitatory Postsynaptic Potentials genetics
Female
Hippocampus cytology
Humans
Male
Mice
Mice, Transgenic
Phosphopyruvate Hydratase metabolism
Rats
Sodium Channel Blockers pharmacology
Synaptic Vesicles metabolism
Synaptic Vesicles pathology
Tetrodotoxin pharmacology
Time Factors
Embryonic Stem Cells physiology
Fragile X Mental Retardation Protein genetics
Fragile X Syndrome genetics
Neurons physiology
Trinucleotide Repeats genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 35
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 26586818
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.0317-15.2015