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Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons

Harley, Peter; Kerins, Caoimhe; Gatt, Ariana; Neves, Guilherme; Riccio, Federica; Machado, Carolina Barcellos; Cheesbrough, Aimee; ... Lieberam, Ivo; + view all (2023) Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons. Cell Reports , 42 (12) , Article 113509. 10.1016/j.celrep.2023.113509. Green open access

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Abstract

Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of in vitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.

Type: Article
Title: Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.celrep.2023.113509
Publisher version: https://doi.org/10.1016/j.celrep.2023.113509
Language: English
Additional information: © 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Axon initial segment, ALS, TDP-43, C9orf72, hyperexcitability, homeostatic plasticity, motor neuron, motor unit, fasciculations, human iPSC, optogenetic
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10182511
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