Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons
Peter Harley,
Caoimhe Kerins,
Ariana Gatt,
Guilherme Neves,
Federica Riccio,
Carolina Barcellos Machado,
Aimee Cheesbrough,
Lea R’Bibo,
Juan Burrone,
Ivo Lieberam
Affiliations
Peter Harley
Centre for Gene Therapy & Regenerative Medicine, Kings College London, London SE1 9RT, UK; Centre for Developmental Neurobiology, Kings College London, London SE1 1UL, UK; UCL Queen Square Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK
Caoimhe Kerins
Centre for Gene Therapy & Regenerative Medicine, Kings College London, London SE1 9RT, UK; Centre for Developmental Neurobiology, Kings College London, London SE1 1UL, UK; Centre for Craniofacial & Regenerative Biology, King’s College London, London SE1 9RT, UK
Ariana Gatt
Queen Square Brain Bank, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 1PJ, UK
Guilherme Neves
Centre for Developmental Neurobiology, Kings College London, London SE1 1UL, UK
Federica Riccio
Centre for Gene Therapy & Regenerative Medicine, Kings College London, London SE1 9RT, UK; Centre for Developmental Neurobiology, Kings College London, London SE1 1UL, UK
Carolina Barcellos Machado
Centre for Gene Therapy & Regenerative Medicine, Kings College London, London SE1 9RT, UK; Centre for Developmental Neurobiology, Kings College London, London SE1 1UL, UK
Aimee Cheesbrough
Centre for Gene Therapy & Regenerative Medicine, Kings College London, London SE1 9RT, UK; Centre for Developmental Neurobiology, Kings College London, London SE1 1UL, UK
Lea R’Bibo
Centre for Gene Therapy & Regenerative Medicine, Kings College London, London SE1 9RT, UK; Centre for Developmental Neurobiology, Kings College London, London SE1 1UL, UK
Juan Burrone
Centre for Developmental Neurobiology, Kings College London, London SE1 1UL, UK; MRC Centre for Neurodevelopmental Disorders, Kings College London, London SE1 1UL, UK; Corresponding author
Ivo Lieberam
Centre for Gene Therapy & Regenerative Medicine, Kings College London, London SE1 9RT, UK; Centre for Developmental Neurobiology, Kings College London, London SE1 1UL, UK; MRC Centre for Neurodevelopmental Disorders, Kings College London, London SE1 1UL, UK; Corresponding author
Summary: 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.
