Table 1.

Evidence of synaptic dysfunctions observed in ALS and FTD patients and postmortem tissue.

	ALS	FTD
Excitatory system	• Excess glutamate in CSF (Rothstein et al., 1990; Pioro et al., 1999) • Deficient glutamate uptake in the motor cortex, somatosensory cortex, and spinal cord (Rothstein et al., 1992; Bristol and Rothstein, 1996) • Loss of the excitatory amino acid transporter 2 (EAAT2) in postmortem motor cortex (Bristol and Rothstein, 1996) • Downregulation of GluN1, GluN2a, GluN2D, GluA2, and GluA3 transcripts (Aronica et al., 2015) • Upregulation of GluA1, GluN2A, and GluN2B in the frontal cortex, and gene clusters related to neuroinflammation in the spinal cord (Andres-Benito et al., 2017)	• Autoantibodies to GluA3 in the CSF of FTLD-tau patients and reduction of the GluA3 protein in the temporal cortex (Palese et al., 2020) • Increase in GluA2 subunit protein (Palese et al., 2020) • Reduction in intracortical facilitation in patients with GluA3 autoantibodies (Palese et al., 2020) • Increase in serine and glutamate in CSF of FTD-patients (Palese et al., 2020)
Inhibitory system	• Loss of parvalbumin interneurons (Nihei et al., 1993) • Reduction in GABAergic inhibition in the motor cortex (Turner et al., 2005; Foerster et al., 2012) • Reduction of GABAα1 transcripts in postmortem motor, frontal, and temporal cortices (Petri et al., 2006) • Elevated GABAβ1 subunit mRNA in the motor cortex, and mRNA for the enzyme glutamic acid decarboxylase (GAD) is elevated in frontal and temporal cortices (Petri et al., 2003, 2006) • Upregulation of GABBRA1, GABBR2 in frontal cortex (Andres-Benito et al., 2017)	• TMS studies indicate deficits in the inhibitory system in FTD (Benussi et al., 2017)
Synaptic proteins	• Decreased levels of the trans-synaptic organizer neuronal pentraxin receptor (NPTXR) in C9-FTD vs. C9-NRE carriers, which is a trans-synaptic organizer of excitatory and inhibitory synapses (Barschke et al., 2020) • Pre-symptomatic C9-NRE mutation carriers, PET imaging with [11C] UCB-J, which binds to the synaptic vesicle protein, SV2A, revealed a synaptic loss in the thalamus before symptom onset (Malpetti et al., 2021)	• Neuronally derived exosomes isolated from FTD patient plasma have reduced levels of synaptotagmin, synaptophysin, and neurogranin, and increase of pre-synaptic synapsin-1 protein (Goetzl et al., 2016)
Morphological defects	• Apical dendrites, in addition to the cell bodies of Betz cells in layer V degenerate in the cortex of ALS patients (Udaka et al., 1986) • Apical dendrite degeneration of Betz cells in fALS, sALS, and FTD-ALS (Genc et al., 2017) • Significant reduction in the number of synapses in motor cortex (Genc et al., 2017) • Loss of synapses in pre-frontal cortex correlating with severity of cognitive impairment (Henstridge et al., 2018) • Selective loss of tripartite synapses in the spinal cord of C9-NRE patients (Broadhead et al., 2022)	• Decreased density of dendritic spines on layer III pyramidal cells in the postmortem cortex (Catala et al., 1988; Ferrer, 1999), • Degeneration of dendrites of the dentate gyrus (Terreros-Roncal et al., 2019) • Severe reduction in dendritic arborization and spine density in upper cortical layers (Ferrer et al., 1991)
Functional studies	• Cortical hyperexcitability is observed in ALS patients (Eisen et al., 1993; Kanai et al., 2006; Vucic and Kiernan, 2006; Vucic et al., 2008; Bae et al., 2013; Geevasinga et al., 2015, 2016; Wainger and Cudkowicz, 2015; Walhout et al., 2015; Schanz et al., 2016; Brunet et al., 2020; Menon et al., 2020).	• Hyperexcitability is yet not observed in the C9-FTD patient populations (Schanz et al., 2016)

These dysfunctions include defects in excitatory and inhibitory neurotransmitter systems, and changes in synaptic protein levels.