Hyperexcitability in synaptic and firing activities of spinal motoneurons in an adult mouse model of amyotrophic lateral sclerosis

Abstract

Hyperexcitability is hypothesized to contribute to the degeneration of spinal motoneurons (MNs) in amyotrophic lateral sclerosis (ALS). Studies, thus far, have not linked hyperexcitability to the intrinsic properties of MNs in the adult ALS mouse model with the G93A-mutated SOD1 protein (mSOD1G93A). In this study, we obtained two types of measurements: ventral root recordings to assess motor output and intracellular recordings to assess synaptic properties of individual MNs. All studies were carried out in an in vitro preparation of the sacral spinal cords of mSOD1G93A mice and their non-transgenic (NT) littermates, both in the age range of 50 – 90 days. Ventral root recordings revealed that maximum compound action potentials (coAPs) evoked by a short-train stimulation of corresponding dorsal roots were similar between the two types of mice. Although the progressive depression of coAPs was present during the train stimulation in all recordings, the coAP depression in mSOD1G93A mice was to a lesser extent, which suggests an increased firing tendency in mSOD1G93A MNs. Intracellular recordings showed no changes in fast excitatory postsynaptic potentials (EPSPs) in mSOD1G93A MNs. However, recording did show that oscillating EPSPs (oEPSPs) were induced by poly-EPSPs at a higher frequency and by less-intense electrical stimulation in mSOD1G93A MNs. These oEPSPs were dependent upon the activities of spinal network and N-methyl-D-aspartate receptors (NMDARs), and were subjected to riluzole modulation. Taken together, these findings revealed abnormal electrophysiology in mSOD1G93A MNs that could underlie ALS excitotoxicity.

Impact of aging on diaphragm muscle function in male and female Fischer 344 rats

“…; Jiang et al. ). The enhancement of mitochondrial fusion and/or the inhibition of mitochondrial fragmentation ameliorates neuronal degeneration in ALS models (Song et al.…”

Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology

“…induced pluripotent stem cell (IPSC)-derived MN from patient fibroblasts (Sareen et al, 2013;Wainger et al, 2014;Devlin et al, 2015;Naujock et al, 2016), cultured MN derived from spinal cord of early postnatal or embryonic mice (Pieri, 2003;Kuo et al, 2004;Kuo et al, 2005;Martin et al, 2013) or acutely isolated spinal cord/brain stem slices (Kuo et al, 2004;Bories et al, 2007;van Zundert et al, 2008;Pambo-Pambo et al, 2009;Quinlan et al, 2011;Martin et al, 2013;Leroy et al, 2014;Jiang et al, 2017; Figure 3 and Tables 3, 4). Thanks to recent advances in stem cell research, it is now possible to study the excitability and activity of MN derived from human patients' fibroblasts through the generation of IPSC.…”

“…Furthermore, a substantial fraction of those had lost their ability to fire repetitively, arguing for the hypoexcitability of LMN in early stages in vivo (Delestrée et al, 2014). Seemingly at odds with these findings, are data pointing toward increased excitability of LMN (prolonged repetitive firing and higher frequency of spontaneous EPSPs) upon the stimulation of the dorsal root in acutely isolated sacral spinal cords obtained from presymptomatic − early symptomatic (P50−P90) SOD1 G93A tg mice (Jiang et al, 2017). Interestingly, based on pharmacological testing Jiang et al propose that the observed changes in spontaneous depolarization originate at least in part from spinal network inputs rather than through the peripheral afferents (Jiang et al, 2017).…”

“…Seemingly at odds with these findings, are data pointing toward increased excitability of LMN (prolonged repetitive firing and higher frequency of spontaneous EPSPs) upon the stimulation of the dorsal root in acutely isolated sacral spinal cords obtained from presymptomatic − early symptomatic (P50−P90) SOD1 G93A tg mice (Jiang et al, 2017). Interestingly, based on pharmacological testing Jiang et al propose that the observed changes in spontaneous depolarization originate at least in part from spinal network inputs rather than through the peripheral afferents (Jiang et al, 2017). Given the differences in sample preparation, recording technique, stimulation procedure and age of the animals, a decisive conclusion remains unattainable at the moment.…”

“…Despite ample evidence indicating changes in intrinsic excitability of motor neurons (likely via cell autonomous mechanisms), there is also data arguing for altered synaptic inputs (non-cell autonomous processes) (Fogarty et al, 2015;Jiang et al, 2017). As neuronal activity hinges on both parameters, we will summarize the current knowledge of sources providing synaptic inputs and how these might be affected by disease pathology.…”