MaxWell Webinars

Impaired Activity in Motor Neurons modeling ALS with Daniel Sommer

4th October 2022

Watch the replay

Title 

Aging-Dependent Altered Transcriptional Programs Underlie Activity Impairments in Human C9orf72-Mutant Motor Neurons

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, affecting both upper and lower motor neurons (MN) and that leads to death typically within 3-5 years following diagnosis. Even though previous studies revealed that alterations in synapses and neuronal activity are part of the underlying pathomechanisms in both in vitro and in vivo models, their specific contribution to neurodegenerative processes is still under debate. Specifically, the influence of neuronal hyper- or hypoactivity on cellular disease progression is highly controversial since both phenotypes have been described and found to be harmful in ALS MN.

Methods: We employed high density multielectrode array (HD-MEA) techniques to longitudinally monitor the electrophysiological properties of hiPSC-derived C9orf72-mutant and healthy MN. To gain further insight into molecular causes triggering activity alterations in mutant motor neurons, we combined this data with corresponding transcriptome analyses. Finally, we sought to rescue the observed phenotype by administration of the SK channel blocker Apamin.

Results: In our study, we found an early hyperactivity of ALS^C9orf72 MN, which drastically decreased upon neuronal aging and was no longer evident when neurodegeneration started to occur. In accordance with previous publications describing synaptic loss in ALS MN, we could furthermore observe a generally reduced network synchroneity in ALS^C9orf72 MN cultures. Consistent with our HD-MEA findings, we observed an up-regulation of synaptic transcripts in ALS^C9orf72 MN at the earlier time point, which was followed by a significant reduction over time. By administration of the SK channel inhibitor Apamin, which has previously been shown to be neuroprotective in ALS MN, we were able to achieve beneficial effects on an electrophysiological as well as transcriptional level.

Conclusion: Altogether, this study suggests phenomena of synaptic maturation as possible explanation for contradicting evidence on electrophysiological alterations in ALS^C9orf72 MN, provides an insight into the longitudinal development of their neuronal activity and links these functional changes to aging-dependent transcriptional programs.

Recent Publications

Aging-Dependent Altered Transcriptional Programs Underlie Activity Impairments in Human C9orf72-Mutant Motor Neurons 

Daniel Sommer, Sandeep Rajkumar, Mira Seidel, Amr Aly, Albert Ludolph, Ritchie Ho, Tobias M. Boeckers and Alberto Catanese

Frontiers in Molecular Neuroscience, June 2022

(DOI: https://doi.org/10.3389/fnmol.2022.894230)

Speaker Bio

Daniel Sommer, MD student at Ulm University, member of the AG Catanese (Institute of Anatomy and Cell Biology, directed by Prof. Dr. T. M. Böckers)

Watch Previous Webinars