Homeostatic Dysregulation in Membrane Properties of Masticatory Motoneurons Compared with Oculomotor Neurons in a Mouse Model for Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motoneuron disease with presently no cure. Motoneuron (MN)hyperexcitability is commonly observed in ALS and is suggested to be a precursor for excitotoxic cell death. However, it is unknown whether hyperexcitability also occurs in MNs that are resistant to degeneration. Second, it is unclear whether all the MNs within homogeneous motor pools would present similar susceptibility to excitability changes since high-threshold MNs innervating fast fatigable muscle fibers selectively degenerate compared with low-threshold MNs innervating fatigue resistant slow muscle fibers. Therefore, we concurrently examined the excitability of ALS-vulnerable trigeminal motoneurons (TMNs) controlling jaw musculature and ALSresistant oculomotor neurons (OMNs) controlling eye musculature in a well studied SOD1 G93A ALS mouse model using in vitro patchclamp electrophysiology at presymptomatic ages P8 -P12. Our results show that hyperexcitability is not a global change among all the MNs, although mutant SOD1 is ubiquitously expressed. Instead, complex changes occur in ALS-vulnerable TMNs based on motor unit type and discharge characteristics. Firing threshold decreases among high-threshold TMNs and increases in a subpopulation of lowthreshold TMNs. The latter group was identified based on their linear frequency-current responses to triangular ramp current injections. Such complex changes in MN recruitment were absent in ALS-resistant OMNs. We simulated the observed complex changes in TMN excitability using a computer-based jaw closer motor pool model. Model results suggest that hypoexcitability may indeed represent emerging disease symptomology that causes resistance in muscle force initiation. Identifying the cellular and molecular properties of these hypoexcitable cells may guide effective therapeutic strategies in ALS.

Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1G93AMouse Model for ALS

“…Although non-motor and non-cell autonomous triggers have been implicated for MN death in ALS (Boillée et al, 2006a), to date, there is no direct evidence for exclusive circuit elements showing intrinsic electrophysiological abnormalities. In combination with our previous report on early dysregulation of MN excitability (Venugopal et al, 2015), the present results implicate a defective sensorimotor network in ALS, which may represent a convergent neuroanatomical pathway across multiple neurodegenerative motor neuron diseases.…”

“…In this study, we focused on SOD1 G93A mutation-induced modifications to proprioceptive sensory neurons (Mes V cells), at an early time point when MN dysregulation was previously reported (Venugopal et al, 2015). There are four main findings: 1) an early circuit-specific reduced excitability exclusively in the trigeminal proprioceptive sensory neurons in comparison with mechanoreceptive, nociceptive and visual sensory neurons in age-matched mSOD1 mice, 2) impaired bursting in the proprioceptive Mes V neurons associated with a down-regulation of Nav1.6 Na + currents and ion channels, 3) rescue of normal burst patterns in the mSOD1 Mes V neurons upon restoration of Na + currents, and, 4) computational model-based prediction of an effect of aberrant sensory gating on motor neuron discharge patterns.…”

“…The excitatory postsynaptic current was included in the dendritic compartment of the TMN model and is given by the following conductance-based equation: where, V d is the TMN dendritic voltage, and, V e = −20 mV, is the reversal potential for an excitatory synaptic current. The value of maximal synaptic conductance, g syn was set such that presynaptic Mes V bursts generated postsynaptic TMN firing frequencies in the range observed in SOD1 G93A TMNs (Venugopal et al, 2015).…”

“…Secondly, MNs that control eye movements (oculomotor, trochlear and abducens) and sphincter muscles (Onuf’s nucleus), as well as gamma MNs that innervate intrafusal muscle fibers are selectively resistant to death (Iwata and Hirano, 1978; Ferrucci et al, 2010; Lalancette-Hebert et al, 2016). Comparative analyses have highlighted important differences in transcriptional profiles, electrical and synaptic properties, and, neuromuscular biology and innervation patterns between the resistant and vulnerable MNs (Frey et al, 2000; Nimchinsky et al, 2000; Hedlund et al, 2010; Comley et al, 2015; Venugopal et al, 2015; Nijssen et al, 2017). These inherent differences indicate local and long-range defects in sensorimotor circuits of vulnerable MNs in ALS (Durand et al, 2006).…”

“…To test whether circuit-specific dysfunction involves proprioceptive sensory neurons, we leveraged the unique architecture of the brainstem trigeminal sensorimotor circuitry involved in jaw control. We examined the proprioceptive Ia afferents in the pontine mesencephalic nucleus (Mes V) in the SOD1 G93A mouse model at P11±3 when the jaw motor pools are reported to be dysregulated (Venugopal et al, 2015). Our results show that Mes V neurons present electrical abnormalities and arrhythmic burst discharge patterns, associated with a marked reduction in Nav1.6-type Na + currents.…”