Excessive Homeostatic Gain in Spinal Motoneurons in a Mouse Model of Amyotrophic Lateral Sclerosis

Abstract

In the mSOD1 model of ALS, the excitability of motoneurons is poorly controlled, oscillating between hyperexcitable and hypoexcitable states during disease progression. The hyperexcitability is mediated by excessive activity of voltage-gated Na+ and Ca2+ channels that is initially counteracted by aberrant increases in cell size and conductance. The balance between these opposing actions collapses, however, at the time that the denervation of muscle fibers begins at about P50, resulting in a state of hypo-excitability and cell death. We propose that this process of neurodegeneration ensues from homeostatic dysregulation of excitability and have tested this hypothesis by perturbing a signal transduction pathway that plays a major role in controlling biogenesis and cell size. Our 『homeostatic dysregulation hypothesis' predicted that neonatal mSOD1 motoneurons would be much more sensitive to such perturbations than wild type controls and our results strongly support this hypothesis. Our results have important implications for therapeutic approaches to ALS.

Response to Letter to Editor on the article Jensen DB, Kadlecova M, Allodi I, Meehan CF (2020)

“…2), just as previously. We realise that changes in multiple parameters, which may obscure each other, might be occurring in the motoneurons of these mice, perhaps controlled by homeostatic mechanisms, as in the younger animals investigated by Kuo et al (2020). Nevertheless, the above observations do not support the hypothesis that the increase in motoneuron responsiveness in this model of ALS is simply due to a loss of large motoneurons.…”

Size‐dependent dendritic maladaptations of hypoglossal motor neurons in SOD1G93A mice

“…However, intrinsic excitability also critically depends on the nonlinear nature and density of various ionic channels expressed in the dendrites (Binder, Powers, & Heckman, 2020). For example, SOD1 MNs has been shown to express increased persistent inward currents (Kuo, Binder, & Heckman, 2020;Kuo, Siddique, Fu, & Heckman, 2005;van Zundert et al, 2008). Increased dendritic spine numbers provide for the maintenance of aforementioned unitary synaptic inputs, although in hypoglossal MNs of SOD1 mice (Fogarty, Mu, et al, 2017), increased dendritic spine density may actually result in an increase in the unitary synaptic input to larger tertile MNs when compared to wild type.…”

Inhibitory interneurons show early dysfunction in a SOD1 mouse model of amyotrophic lateral sclerosis

“…Notably, MNs derived from ALS patients’ induced pluripotent stem cells also show initial hyperexcitability followed by hypoexcitability (Wainger et al, 2014; Devlin et al, 2015), and increasing excitability of MNs enhanced neuroprotection rather than neurodegeneration (Saxena et al, 2013). A unifying theme throughout the findings is that vulnerable MNs show excessive homeostatic gain in response to perturbation (Kuo et al, 2020), and not only excitability but other cellular properties fluctuate over the lifespan of the animal (Irvin et al, 2015). In light of that, whether inhibitory interneurons are less excitable at other ages should be explored in future studies to fully characterize their contribution to neurodegenerative processes.…”