Cortical hyperexcitability drives dying forward ALS symptoms and pathology in mice

Haidar, Mouna; Viden, Aida; Cuic, Brittany; Wang, Taide; Rosier, Marius; Tomas, Doris; Mills, Samuel A.; Govier-Cole, A; Djouma, Elvan; Luikinga, Sophia J; Rytova, Valeria; Barton, Samantha K.; Gonsalvez, David G.; Palmer, Lucy M.; McLean, Catriona; Kiernan, Matthew C.; Vucic, Steve; Turner, Bradley J.

doi:10.1101/2021.08.13.456320

Cited by 5 publications

(2 citation statements)

References 21 publications

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“…Early cultures with SOD1, C9orfF72 and TARDBP mutations have all exhibited hyperexcitability, with increased spontaneous activity, after which cells later become hypoactive with less synaptic inputs, as disease progresses [44]. A similar evolution of change in excitability has been demonstrated in rodent models of ALS, even in the absence of genetic mutation [45].…”

Section: Altered Motor Neuron Excitability: Mechanistic Insightmentioning

confidence: 69%

Cortical hyperexcitability in amyotrophic lateral sclerosis: from pathogenesis to diagnosis

Timmins

Vucic

Kiernan

2023

Current Opinion in Neurology

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Purpose of review Identification of upper motor neuron involvement remains a critical component of a diagnosis of amyotrophic lateral sclerosis (ALS), although supportive clinical signs are often not easily appreciated, particularly in the early symptomatic stages of the disease. Although diagnostic criteria have been developed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains problematic. Recent findings Recent evidence has emerged about pathophysiological processes, particularly glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the C9orf72 gene, have changed concepts of ALS, from being classified as a neuromuscular disease to a disease that forms a continuum with other primary neurodegenerative disorders, particularly frontotemporal dementia. Transcranial magnetic stimulation has been utilized to provide pathophysiological insights, leading to the development of diagnostic and therapeutic biomarkers, which are now being introduced into the clinical setting. Summary Specifically, the advent of cortical hyperexcitability has been consistently identified as an early and intrinsic feature of ALS. With greater accessibility of TMS techniques promoting clinical utilization, TMS measures of cortical function may develop as a diagnostic biomarker, with further potential utility in the clinical trial setting for monitoring of neuroprotective and genetic-based therapies.

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Section: Altered Motor Neuron Excitability: Mechanistic Insightmentioning

confidence: 69%

Cortical hyperexcitability in amyotrophic lateral sclerosis: from pathogenesis to diagnosis

Timmins

Vucic

Kiernan

2023

Current Opinion in Neurology

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“…Reduced inhibition onto layer V neurons appears to drive hyperexcitability in this neuronal population in TDP-43 A 135 T mice ( Zhang et al, 2016 ). Recent data from a rodent model in which hyperexcitability is chronically chemogenetically driven in upper motor neurons leads to the development of essential features of ALS, including upper and lower motor neuron degeneration, reactive gliosis and induced TDP-43 pathology ( Haidar et al, 2021 ). Such data is consistent with the interrelation between hyperexcitability and the feed forward model of neurodegeneration.…”

Section: Cortical Dysfunction In C9orf72 Repeat Expansion-mediated Amyotrophic Lateral Sclerosis-frontotemporal Dementmentioning

confidence: 99%

Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

Pasniceanu

Atwal

Souza

et al. 2021

Front. Cell. Neurosci.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by degeneration of upper and lower motor neurons and neurons of the prefrontal cortex. The emergence of the C9ORF72 hexanucleotide repeat expansion mutation as the leading genetic cause of ALS and FTD has led to a progressive understanding of the multiple cellular pathways leading to neuronal degeneration. Disturbances in neuronal function represent a major subset of these mechanisms and because such functional perturbations precede degeneration, it is likely that impaired neuronal function in ALS/FTD plays an active role in pathogenesis. This is supported by the fact that ALS/FTD patients consistently present with neurophysiological impairments prior to any apparent degeneration. In this review we summarize how the discovery of the C9ORF72 repeat expansion mutation has contributed to the current understanding of neuronal dysfunction in ALS/FTD. Here, we discuss the impact of the repeat expansion on neuronal function in relation to intrinsic excitability, synaptic, network and ion channel properties, highlighting evidence of conserved and divergent pathophysiological impacts between cortical and motor neurons and the influence of non-neuronal cells. We further highlight the emerging association between these dysfunctional properties with molecular mechanisms of the C9ORF72 mutation that appear to include roles for both, haploinsufficiency of the C9ORF72 protein and aberrantly generated dipeptide repeat protein species. Finally, we suggest that relating key pathological observations in C9ORF72 repeat expansion ALS/FTD patients to the mechanistic impact of the C9ORF72 repeat expansion on neuronal function will lead to an improved understanding of how neurophysiological dysfunction impacts upon pathogenesis.

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How is Excitotoxicity Being Modelled in iPSC-Derived Neurons?

Cheng,

Cook,

Talbot

et al. 2024

Neurotox Res

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Excitotoxicity linked either to environmental causes (pesticide and cyanotoxin exposure), excitatory neurotransmitter imbalance, or to intrinsic neuronal hyperexcitability, is a pathological mechanism central to neurodegeneration in amyotrophic lateral sclerosis (ALS). Investigation of excitotoxic mechanisms using in vitro and in vivo animal models has been central to understanding ALS mechanisms of disease. In particular, advances in induced pluripotent stem cell (iPSC) technologies now provide human cell-based models that are readily amenable to environmental and network-based excitotoxic manipulations. The cell-type specific differentiation of iPSC, combined with approaches to modelling excitotoxicity that include editing of disease-associated gene variants, chemogenetics, and environmental risk-associated exposures make iPSC primed to examine gene-environment interactions and disease-associated excitotoxic mechanisms. Critical to this is knowledge of which neurotransmitter receptor subunits are expressed by iPSC-derived neuronal cultures being studied, how their activity responds to antagonists and agonists of these receptors, and how to interpret data derived from multi-parameter electrophysiological recordings. This review explores how iPSC-based studies have contributed to our understanding of ALS-linked excitotoxicity and highlights novel approaches to inducing excitotoxicity in iPSC-derived neurons to further our understanding of its pathological pathways.

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Cortical hyperexcitability drives dying forward ALS symptoms and pathology in mice

Cited by 5 publications

References 21 publications

Cortical hyperexcitability in amyotrophic lateral sclerosis: from pathogenesis to diagnosis

Cortical hyperexcitability in amyotrophic lateral sclerosis: from pathogenesis to diagnosis

Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia

How is Excitotoxicity Being Modelled in iPSC-Derived Neurons?

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