Early Excitability Changes in Lumbar Motoneurons of Transgenic SOD1^G85Rand SOD1^G93A-LowMice

Abstract

This work characterizes the properties of wild-type (WT) mouse motoneurons in the second postnatal week and compares these at the same age and in the same conditions to those of two different SOD1 mutant lines used as models of human amyotrophic lateral sclerosis (ALS), the SOD1(G93A) low expressor line and SOD1(G85R) line, to describe any changes in the functional properties of mutant motoneurons (Mns) that may be related to the pathogenesis of human ALS. We show that very early changes in excitability occur in SOD1 mutant Mns that have different properties from those of WT animals. The SOD1(G93A-Low) low expressor line displays specific differences that are not found in other mutant lines including a more depolarized membrane potential, larger spike width, and slower spike rise slope. With current pulses SOD1(G93A-Low) were hyperexcitable, but both mutants had a lower gain with current ramps stimulation. Changes in the threshold and intensities of Na(+) and Ca(2+) persistent inward currents were also observed. Low expressor mutants show reduced total persistant inward currents compared with WT motoneurons in the same recording conditions and give arguments toward modifications of the balance between Na(+) and Ca(2+) persistent inward currents. During the second week postnatal, SOD1(G93A-Low) lumbar motoneurons appear more immature than those of SOD1(G85R) compared with WT and we propose that different time course of the disease, possibly linked with different toxic properties of the mutated protein in each model, may explain the discrepancies between excitability changes described in the different models.

Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS

“…Changes in intrinsic properties that make MNs hyperexcitable have been noted in neonatal slice preparations of ALS animals (29), as well as in MNs derived from iPS cells of ALS patients (15). Recent work in vivo, however, has questioned whether changes in intrinsic properties of MNs leads to hyperexcitability in adult animals (30).…”

Clinical Measures of Disease Progression in Amyotrophic Lateral Sclerosis

“…Excitability testing of peripheral nerves has recently garnered increased attention as studies have demonstrated alterations of excitability of motor neurons in ALS [66,67]. In addition, 1 study showed that the degree of excitability at baseline predicted long-term survival in humans, with higher levels of excitability predicting shorter survival [68].…”

Potassium currents dynamically set the recruitment and firing properties of F-type motoneurons in neonatal mice

“…During this week, postural activity is acquired, allowing the locomotor behavior to switch from crawling to walking (Jiang et al 1999). The firing behavior of motoneurons is heterogeneous, and two modes of discharge initiation have been observed during this week (Leroy et al 2014;Pambo-Pambo et al 2009;Russier et al 2003). For liminal current pulses, the discharge starts at the current onset in one-third of spinal motoneurons (immediate-firing pattern) whereas it is delayed in the two other thirds (Leroy et al 2014;Pambo-Pambo et al 2009).…”