TABLE 2.

Summary of physiological studies that have implication for the C9ORF72^RE in lower motor neuron dysfunction.

Lower motor neurons	Study	Physiological finding	Link to C9ORF72RE	Method of investigation	Model
	Donnelly et al., 2013	Increased susceptibility to glutamate-mediated excitotoxicity	Toxic RNA gain-of-function	Transcriptomics; Excitotoxicity assay	C9ORF72RE patient-derived iPSC motor neurons
	Sareen et al., 2013	Intrinsic hypoexcitability		Patch-clamp electrophysiology	C9ORF72RE patient-derived iPSC motor neurons
	Wainger et al., 2014	Hyperexcitability and pharmacological rescue using Kv7 channel activator		Multielectrode array and patch-clamp electrophysiology; Pharmacological rescue	C9ORF72RE patient-derived iPSC motor neurons
	Devlin et al., 2015	Initial intrinsic hyperexcitability, followed by hypoexcitability and loss of synaptic activity		Patch-clamp electrophysiology	C9ORF72RE patient-derived iPSC motor neurons
	Zhang et al., 2015	Impaired synaptic release at the neuromuscular junction	Disruption of normal RNA processing	Patch-clamp electrophysiology	C9ORF72RE patient-derived iPSC motor neurons
		Reduction in active zones number			(C4G2)30 Drosophila model
	Freibaum et al., 2015	Impaired synaptic release at the neuromuscular junction	Disruption of normal RNA processing	Neuronal phenotype analysis	(C4G2)58 Drosophila model
		Reduction in active zones number
	Perry et al., 2017	Impaired synaptic plasticity at the neuromuscular junction	Poly-GR (100 repeat) DPRs	Patch-clamp electrophysiology	C9ORF72RE Drosophila model
	Xu and Xu, 2018	Increased extracellular glutamate and intracellular Ca2+ levels	Poly-GR/PR (36 repeat) DPRs	Glutamate and calcium imaging	C9ORF72RE Drosophila model
		Increased in NMDA receptor mediated signaling
		Increase of synaptic boutons and active zones in larval neuromuscular junctions
	Shi et al., 2018	Increased susceptibility to glutamate-mediated excitotoxicity	C9ORF72 haploinsufficiency	Excitotoxicity; Pharmacological rescue; Immunostaining; Biochemical (Western blot, qPCR)	C9ORF72RE patient-derived iPSC motor neurons
		Increased functional expression of calcium permeable AMPAR
		Upregulation of NMDA receptor subunit GluN1
	Selvaraj et al., 2018	Increased susceptibility to glutamate-mediated excitotoxicity		Patch-clamp electrophysiology; BaseScope Assay; Biochemical (Western blot, qPCR)	C9ORF72RE patient-derived iPSC motor neurons C9ORF72RE post-mortem material
		Increased GluA1 AMPA subunit expression
		Increased functional expression of calcium permeable AMPAR
	Bursch et al., 2019	Increased susceptibility to glutamate-mediated excitotoxicity		Calcium imaging	C9ORF72RE patient-derived iPSC motor neurons
	Gregory et al., 2020	Increased GluA1 AMPA subunit expression selective to motor neurons, not cortical neurons		BaseScope	C9ORF72RE patient post-mortem material
	Zhao et al., 2020	Astrocyte-mediated hypoexcitability		Patch-clamp electrophysiology; Transcriptomics	C9ORF72RE mutant iPSC-derived astrocytes
	Catanese et al., 2021	Hypoexcitability driven loss of excitatory synapses through a CREB-dependent signaling pathway		Transcriptomics; Proteomics; Optogenetics Pharamcological rescue	C9ORF72RE patient-derived iPSC motor neurons
	Castelli et al., 2021	Manipulating SK ion channel activity improves C9ORF72-ALS motor neuron death and Drosophila locomotor deficits		Transcriptomics; Pharmacological rescue	C9ORF72RE patient-derived iPSC motor neurons
					C9ORF72RE Drosophila model
	Butti et al., 2021	Reduction in the number of presynaptic and postsynaptic structures at the NMJ	C9ORF72 haploinsufficiency	Patch clamp electrophysiology;	C9ORF72RE-related zebrafish
				Mass spectrometry

The table describes the main physiological findings of the study, whether they are associated with a mechanism of C9ORF72^RE pathology and upon which models these findings were obtained.