Unknown

Dataset Information

0

Human Neuropsychiatric Disease Modeling using Conditional Deletion Reveals Synaptic Transmission Defects Caused by Heterozygous Mutations in NRXN1.


ABSTRACT: Heterozygous mutations of the NRXN1 gene, which encodes the presynaptic cell-adhesion molecule neurexin-1, were repeatedly associated with autism and schizophrenia. However, diverse clinical presentations of NRXN1 mutations in patients raise the question of whether heterozygous NRXN1 mutations alone directly impair synaptic function. To address this question under conditions that precisely control for genetic background, we generated human ESCs with different heterozygous conditional NRXN1 mutations and analyzed two different types of isogenic control and NRXN1 mutant neurons derived from these ESCs. Both heterozygous NRXN1 mutations selectively impaired neurotransmitter release in human neurons without changing neuronal differentiation or synapse formation. Moreover, both NRXN1 mutations increased the levels of CASK, a critical synaptic scaffolding protein that binds to neurexin-1. Our results show that, unexpectedly, heterozygous inactivation of NRXN1 directly impairs synaptic function in human neurons, and they illustrate the value of this conditional deletion approach for studying the functional effects of disease-associated mutations.

SUBMITTER: Pak C 

PROVIDER: S-EPMC4560990 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

Similar Datasets

2016-01-01 | S-EPMC5343326 | BioStudies
2009-01-01 | S-EPMC2775834 | BioStudies
2019-01-01 | S-EPMC7451045 | BioStudies
2011-01-01 | S-EPMC3204930 | BioStudies
2020-01-01 | S-EPMC7370229 | BioStudies
2014-01-01 | S-EPMC4104334 | BioStudies
2016-01-01 | S-EPMC4731316 | BioStudies
2012-01-01 | S-EPMC3499754 | BioStudies
2010-01-01 | S-EPMC3001124 | BioStudies
2019-01-01 | S-EPMC6371743 | BioStudies