Hyperexcitability in young iPSC-derived C9ORF72 mutant motor neurons is associated with increased intracellular calcium release

Burley, Sarah, Beccano-Kelly, Dayne A. ORCID: https://orcid.org/0000-0003-3592-8354, Talbot, Kevin, Llana, Oscar Cordero and Wade-Martins, Richard 2022. Hyperexcitability in young iPSC-derived C9ORF72 mutant motor neurons is associated with increased intracellular calcium release. Scientific Reports 12 (1) , 7378. 10.1038/s41598-022-09751-3

PDF - Published Version Available under License Creative Commons Attribution. Download (2MB)

Abstract

A large hexanucleotide repeat expansion in the C9ORF72 gene is the most prevalent cause of amyotrophic lateral sclerosis (ALS). To better understand neuronal dysfunction during ALS progression, we studied motor neuron (MN) cultures derived from iPSC lines generated from C9ORF72 (C9) expansion carriers and unaffected controls. C9 and control MN cultures showed comparable mRNA levels for MN markers SMI-32, HB9 and ISL1 and similar MN yields (> 50% TUJ1/SMI-32 double-positive MNs). Using whole-cell patch clamp we showed that C9-MNs have normal membrane capacitance, resistance and resting potential. However, immature (day 40) C9-MNs exhibited a hyperexcitable phenotype concurrent with increased release of calcium (Ca2+) from internal stores, but with no changes to NaV and KV currents. Interestingly, this was a transient phenotype. By day 47, maturing C9-MNs demonstrated normal electrophysiological activity, displaying only subtle alterations on mitochondrial Ca2+ release. Together, these findings suggest the potential importance of a developmental component to C9ORF72-related ALS.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Nature Research
ISSN:	2045-2322
Date of First Compliant Deposit:	1 July 2022
Date of Acceptance:	21 February 2022
Last Modified:	26 May 2023 14:17
URI:	https://orca.cardiff.ac.uk/id/eprint/150947

Citation Data

Cited 5 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item