TABLE 3.
Summary of the main physiological observations that are associated with ALS.
| Physiological observation | Evidence in non-C9ORF72RE ALS-FTD | Evidence in C9ORF72RE ALS-FTD |
| Patient cortical hyperexcitability | Established as a hallmark observation in ALS, including sporadic (reviewed Geevasinga et al., 2016). Evidenced pre-symptomatically (Geevasinga et al., 2016; Menon et al., 2017), and prominence increases with disease onset (Menon et al., 2020). Evidenced in FTD patients (Lindau et al., 2003; Nishida et al., 2011) and associated with cognitive decline. | Motor cortical hyperexcitability evidenced in C9ORF72RE ALS (Williams et al., 2013; Benussi et al., 2016; Schanz et al., 2016; Nasseroleslami et al., 2019). Increased strength of cortical hyperexcitability observed in ALS-FTD patients correlates with increased cognitive impairments (Agarwal et al., 2021). |
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| Altered neuronal plasticity | Hippocampal synaptic plasticity was evidenced in murine models: UBQLN2P497H(Gorrie et al., 2014); SOD1G93A (Spalloni et al., 2011); TDP-43 transgenic mice (Koza et al., 2019), TDP-43 conditional knockout mice (Wu et al., 2019); non-TDP-43 FTD models (progranulin knock out mice (Petkau et al., 2012) and MAPT knockout (Ahmed et al., 2014; Biundo et al., 2018). | Patient synaptic/network plasticity observations are present in presymptomatic disease stages (Benussi et al., 2016). Synaptic plasticity defects are highlighted in iPSC-derived C9ORF72RE cortical neurons (Perkins et al., 2021) and C9ORF72RE postmortem cortex (Prudencio et al., 2015). Impaired plasticity at the neuromuscular junction of C9ORF72RE Drosophila (Perry et al., 2017). |
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| Presymptomatic changes in cortical neurophysiological function | Increase in synaptic input and intrinsic excitability in murine models of SOD1G93A (Kim et al., 2017). Reduction in cortical interneurons in TDP-43Q331K knock-in mouse (Lin et al., 2021). Cortical hyperexcitability observed in FTDP-17 mouse model of FTD (García-Cabrero et al., 2013). | Elevated network burst activity and enhanced synaptic input was found in iPSC-derived C9ORF72RE cortical neurons, linked with decreased synaptic density, but not altered intrinsic excitability (Perkins et al., 2021). |
| TDPA315T mouse model show sustained hyperexcitability in somatostatin-positive interneurons, but hypoexcitability in parvalbumin-positive neurons (Zhang et al., 2016). | ||
| Increased synaptic input of excitatory cortical neurons was evidenced in the motor cortex of pre-symptomatic mutant TDP-43Q331K mice and SODG93A mice (Van Zundert et al., 2008; Fogarty et al., 2016a; Saba et al., 2016). Presymptomatic excitability changes in ALS models reviewed in Gunes et al., 2020. | ||
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| Post-symptomatic cortical neurophysiological function | Decreased in synaptic input in ALS post-mortem tissue (Hammer et al., 1979; Genç et al., 2017) and other models, including TDP-43A315T (Handley et al., 2017), SOD1G93A (Fogarty et al., 2016b,2017), and FUSR521G (Sephtona et al., 2014). | Synaptic loss was found to correlate with cognitive decline (Henstridge et al., 2018; Lall et al., 2021). Synaptic loss was observed in the prefrontal cortex of aged (4.5 months) transgenic mice expressing 80-repeat GR (GR80) DPRs (Choi et al., 2019). |
| TDP-43 mouse model shows intrinsic hyperexcitability and decreased excitatory synaptic inputs (Dyer et al., 2021). | Hippocampal regions of 3-month-old C9ORF72 knockout mice show a reduction in synaptic density (Xiao et al., 2019). | |
| Symptomatic TDP-43A315T mice exhibit layer V projection neurons with a decrease in synaptic input and spine density (Handley et al., 2017). Post-symptomatic excitability changes in ALS models reviewed in Gunes et al. (2020). | ||
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| Patient lower motor neuron excitability | Axonal hyperexcitability and decreased function with symptomatic onset was reported in sporadic ALS patients (Geevasinga et al., 2015). Increased motor unit excitability, increased presence of fasciculation potentials, single unit motor unit firing, increased axonal excitability (reviewed in Gunes et al., 2020). | Increased axonal excitability has been highlighted in symptomatic C9ORF72RE ALS patients (Geevasinga et al., 2015). |
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| Models of lower motor neuron intrinsic excitability | Evidence of early hyperexcitability was seen in mSOD1 models (reviewed in Gunes et al., 2020). | Evidence of hyperexcitability at early stages of motor neuron differentiation (Devlin et al., 2015; Wainger and Cudkowicz, 2015) switching to hypoexcitability with culture time (Sareen et al., 2013; Devlin et al., 2015; Zhang et al., 2015; Naujock et al., 2016; Guo et al., 2017). |
| Shifting excitability in mutant SOD1 mice motor neurons that display a period of early hyperexcitability before hypoexcitability (Leroy and Zytnicki, 2015) preceding motor neuron denervation (Martínez-Silva et al., 2018). SOD1G93A expressing astrocytes was found to alter ion channel function and motor neuron excitability (Fritz et al., 2013). |
Increased excitability via pharmacological inhibition of small conductance calcium-activated potassium (SK) channels promotes survival and restores the activity-dependent transcriptional profiles and synaptic composition in iPSC-derived C9ORF72RE motor neurons, and furthermore, promotes locomotor function in a Drosophila model containing 36 hexanucleotide repeats (Castelli et al., 2021; Catanese et al., 2021). | |
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| Loss of motor neuron synaptic input | Synaptic changes in ALS models reviewed in Gunes et al. (2020). | Decreased synaptic activity and spontaneous post-synaptic current activity was evidenced in iPSC-derived C9ORF72RE motor neurons (Devlin et al., 2015). |
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| Loss of NMJ function and innervation | mTDP-43 Drosophila shows synaptic vesicle cycling defects (Coyne et al., 2017). | C9ORF72RE Drosophila over-expressing hexanucleotide repeats (58- and 30-repeats) exhibit impaired synaptic release at the neuromuscular junction and decrease in number of active zones (Freibaum et al., 2015; Zhang et al., 2015). Decreased synaptic arborization and active zone number at neuromuscular junction in C9ORF72RE patient-derived motor neurons (Perry et al., 2017). Impaired vesicle dynamics that precede motor neuron loss have been evidenced in GA mouse model and C9ORF72RE patient-derived motor neurons (Jensen et al., 2020). |
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| Glutamate excitability | mSOD1 patients and models exhibit vulnerability to glutamate-mediated excitotoxicity (Shaw, 2005; Van Den Bosch et al., 2006). | C9ORF72RE patient-derived iPSC motor neurons exhibit enhanced vulnerability to glutamate receptor-mediated excitotoxicity (Donnelly et al., 2013; Selvaraj et al., 2018; Shi et al., 2018; Bursch et al., 2019). C9ORF72RE post-mortem demonstrated that the dysregulation of GluA1 is selective to C9ORF72RE lower motor neurons and is not present in the cortex (Selvaraj et al., 2018; Gregory et al., 2020). |
| GluA1 dysregulation is evidenced in mutant TDP-43 motor neurons (Bursch et al., 2019), FUS (Udagawa et al., 2015) and in sporadic ALS patients (Gregory et al., 2020). Inefficient RNA editing of GluA2 subunits in sporadic ALS patients (Kawahara et al., 2004a). | ||
The table details the prominent pathophysiological concepts that are thought to play a role in the pathogenesis of ALS; for example, cortical hyperexcitability and glutamate dysfunction in lower motor neurons. We summarize papers that provide data in non-C9ORF72RE models and contrast these in current C9ORF72RE models.