Skip to main content
. 2020 Jun 17;14:573. doi: 10.3389/fnins.2020.00573

FIGURE 2.

FIGURE 2

ALS-associated alterations in ventral spinal cord circuitry. LMN receive inhibitory input via Ia-IN, Ib-IN, and RC, and excitatory inputs from cortiospinal tract (UMN), II-IN and SN. γ-motor neurons, which are spared in ALS, do not receive direct inputs from Ia-SN. Excitatory inputs to LMNs via Ia afferent terminals are controlled by PI-IN. Both excitatory and inhibitory inputs are tightly regulated by the proprioceptive feedback provided by sensory afferents (Ia, Ib and II-SN) and astrocytes. Axonal hyperexcitability and hypoexcitability are reported in ALS patients. Decreased RC synapses on LMN and lower number of RC is reported. LMN hypoexcitability is present in vivo in SOD1G93A tg mouse model. Ia-SN neurons exhibit irregular firing patterns as an indication of their altered excitability/activity. Cholinergic C-bouton number is decreased in sALS patients, but C-boutons are enlarged especially onto vulnerable FF LMN in SOD1G93A tg mice. Protein and mRNA levels of ChAT are decreased in spinal cord of ALS patients. Reduced ChAT expression is reported in II-IN and C-boutons on MN of SOD1G93A tg mice. Serotonergic boutons on LMN are increased in low-copy SOD1G93A tg mice, whereas serotonergic neurons in brainstem degenerate in both ALS patients and SOD1G86R tg (not shown). Please note that monosynaptic connections between UMN and LMN are only present in humans. Neuromodulatory synapses are depicted as one (somata located in brainstem). CPGs and descending reticulospinal tract projections to LMN via commissural INs are not depicted for simplicity. Studies with unspecified type of ALS are referred to as (ALS). AP, action potential; AS, astrocytes; CMAP, compound muscle action potential; ChAT, choline acetyltransferase; CPG, central pattern generator; DD, double-discharge; fALS, familial ALS; FF, fast-fatigable; FP, fasciculation potential; FR, fast-resistant; gamma (γ)-motor neuron, γ-MN; GAD65/67, glutamic acid decarboxylase 65/67; Glu, glutamate; GlyT2, glycine transporter 2; Ia-/Ib-IN, class Ia/Ib spinal interneuron; II-IN, class II spinal interneuron; LMN, lower motor neuron; MU, motor unit; NE, norepinephrine; Ia-/Ib-SN, class Ia/Ib sensory neuron; II-SN, class II sensory neuron; PI-IN, presynaptic inhibitory interneuron; RC, Renshaw cell; sALS, sporadic ALS; SOD1, superoxide dismutase 1; S, slow; TEd, depolarizing threshold electrotonus; TEh, hyperpolarizing threshold electrotonus; τSD, strength-duration constant, UMN, upper motor neuron; VGAT, vesicular GABA transporter; VGLUT, vesicular glutamate transporter 2; 5-HT, serotonin. 1(Kostera-Pruszczyk et al., 2002); 2(Kanai et al., 2006); 3(Vucic and Kiernan, 2006); 4(Vucic et al., 2009); 5(Bostock et al., 1995); 6(Horn et al., 1996); 7(Mogyoros et al., 1998); 8(Tamura et al., 2006); 9(Nakata et al., 2006); 10(Piotrkiewicz et al., 2008); 11(de Carvalho and Swash, 2013); 12(Raynor and Shefner, 1994); 13(Hayashi et al., 1981); 14(Whitehouse et al., 1983); 15(Howells et al., 2018); 16(Delestrée et al., 2014); 17(Martínez-Silva et al., 2018); 18(Chang and Martin, 2009); 19(Chang and Martin, 2011a); 20(Chang and Martin, 2011b); 21(Seki et al., 2019); 22(Heads et al., 1991); 23(Hammad et al., 2007); 24(Pugdahl et al., 2007); 25(Sangari et al., 2016); 26(Guo et al., 2009); 27(Sassone et al., 2016); 28(Nagao et al., 1998); 29(Oda et al., 1995); 30(Virgo et al., 1992); 31(Casas et al., 2013); 32(Pullen and Athanasiou, 2009); 33(Saxena et al., 2013); 34(Dentel et al., 2012); 35(Hossaini et al., 2011); 36(Sunico et al., 2011).