Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction
Open accessAbstract
Background: Physiological disturbances in cortical network excitability and plasticity are established and widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those harbouring the C9ORF72 repeat expansion (C9ORF72RE) mutation – the most common genetic impairment causal to ALS and FTD. Noting that perturbations in cortical function are evidenced pre-symptomatically, and that the cortex is associated with widespread pathology, cortical dysfunction is thought to be an early driver of neurodegenerative disease progression. However, our understanding of how altered network function manifests at the cellular and molecular level is not clear. Methods: To address this we have generated cortical neurons from patient-derived iPSCs harbouring C9ORF72RE mutations, as well as from their isogenic expansion-corrected controls. We have established a model of network activity in these neurons using multi-electrode array electrophysiology. We have then mechanistically examined the physiological processes underpinning network dysfunction using a combination of patch-clamp electrophysiology, immunocytochemistry, pharmacology and transcriptomic profiling. Results: We find that C9ORF72RE causes elevated network burst activity, associated with enhanced synaptic input, yet lower burst duration, attributable to impaired pre-synaptic vesicle dynamics. We also show that the C9ORF72RE is associated with impaired synaptic plasticity. Moreover, RNA-seq analysis revealed dysregulated molecular pathways impacting on synaptic function. All molecular, cellular and network deficits are rescued by CRISPR/Cas9 correction of C9ORF72RE. Our study provides a mechanistic view of the early dysregulated processes that underpin cortical network dysfunction in ALS-FTD. Conclusion: These findings suggest synaptic pathophysiology is widespread in ALS-FTD and has an early and fundamental role in driving altered network function that is thought to contribute to neurodegenerative processes in these patients. The overall importance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic plasticity, synaptic vesicle stores, and network propagation, which directly impact upon cortical function.
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The combination of NPTX2, NfL, and GFAP reflects the complexity of pathological mechanisms involved in neurodegenerative disorders and FTD in particular.
“The combination of NPTX2 (representing synaptic plasticity [35]), NfL (marker for overall neurodegeneration [60, 61]), and GFAP (depicting astrogliosis [62]) reflects the complexity of pathological mechanisms involved in neurodegenerative disorders and FTD in particular [63–66]”
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- Authors
- Perkins, E. M., Burr, K., Banerjee, P., Mehta, A. R., Dando, O., Selvaraj, B. T., Suminaite, D., Nanda, J., Henstridge, C. M., Gillingwater, T. H., Hardingham, G. E., Wyllie, D. J. A., Chandran, S., & Livesey, M. R.
- Affiliations
- Euan MacDonald Centre for Motor Neuron Disease Research (GB)
- UK Dementia Research Institute (GB)
- University of Dundee (GB)
- Institute for Stem Cell Biology and Regenerative Medicine (IN)
- Simons Initiative for the Developing Brain (GB)
- Corresponding author
- Chandran, Siddharthan
- Livesey, Matthew R.
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2021-03-04
- Volume
- 16
- Issue
- 1
- Pages
- 13-13
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC7931347
- OpenAlex
- W3135140647
- Cited by
- 54
- References
- 66
- Citations by year
- 2026: 11 · 2025: 5 · 2024: 8 · 2023: 11 · 2022: 14 · 2021: 5
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, cc-by)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Wellcome Trust (092742/Z/10/Z, 092742)
- MND Scotland
- Alzheimer's Society
- International Seafood Sustainability Foundation
- Motor Neurone Disease Association (MEHTA/JUL17/948-795, MR/R001162/1)
- Rosetrees Trust (Seedcorn2020 100144)
- University of Edinburgh
- Department of Biotechnology, Ministry of Science and Technology, India
- UK Dementia Research Institute
- Medical Research Council (MR/L023784/2, MR/R001162/1)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- C9orf72 repeat expansion, amyotrophic lateral sclerosis, frontotemporal dementia, synaptic dysfunction, synaptic plasticity, iPSC-derived cortical neurons, CRISPR/Cas9 gene correction, RNA-seq, neurodegeneration
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Humans, Motor Neurons, Mutation, Neurodegenerative Diseases, DNA Repeat Expansion, Induced Pluripotent Stem Cells, Frontotemporal Dementia
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