Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis

Abstract

In amyotrophic lateral sclerosis (ALS) the large motoneurons that innervate the fast-contracting muscle fibers (F-type motoneurons) are vulnerable and degenerate in adulthood. In contrast, the small motoneurons that innervate the slow-contracting fibers (S-type motoneurons) are resistant and do not degenerate. Intrinsic hyperexcitability of F-type motoneurons during early postnatal development has long been hypothesized to contribute to neural degeneration in the adult. Here, we performed a critical test of this hypothesis by recording from identified F- and S-type motoneurons in the superoxide dismutase-1 mutant G93A (mSOD1), a mouse model of ALS at a neonatal age when early pathophysiological changes are observed. Contrary to the standard hypothesis, excitability of F-type motoneurons was unchanged in the mutant mice. Surprisingly, the S-type motoneurons of mSDO1 mice did display intrinsic hyperexcitability (lower rheobase, hyperpolarized spiking threshold). As S-type motoneurons are resistant in ALS, we conclude that early intrinsic hyperexcitability does not contribute to motoneuron degeneration.DOI: http://dx.doi.org/10.7554/eLife.04046.001

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

“…Indeed the delayed-firing pattern was somehow converted into immediatefiring pattern [no delay in the first spike, firing frequency that does not increase anymore but rather tends to decrease, enlarged spikes-compare inset in Fig. 3, B1 and B2-consistent with our previous observation that immediate-firing motoneurons display larger spikes than delayed-firing motoneurons (Leroy et al 2014)]. Moreover, the rheobase was lowered from 1 nA to less than 0.4 nA following the application of TEA (Fig.…”

“…Indeed, the immediate-firing motoneurons have a smaller input conductance, a lower rheobase, and a longer afterhyperpolarization (AHP) than the delayed-firing motoneurons (Leroy et al 2014). This is in keeping with electrical differences between S-and F-type motoneurons in adult cats (Burke 1981;Zengel et al 1985), rats (Beaumont and Gardiner 2002;Button et al 2006), and mice (Manuel and Heckman 2011).…”

“…During liminal pulses, we observed delays before firing that could last several seconds after the pulse onset (Leroy et al 2014). Here we showed that the firing delay is due to two potassium currents that act at two different time scales.…”

“…We recently showed that motoneurons innervating slowcontracting fibers (S-type motoneurons) selectively display the immediate-firing pattern in neonates, whereas those innervating fast-contracting fibers (F-type motoneurons) display the delayed-firing pattern (Leroy et al 2014). Indeed, the immediate-firing motoneurons have a smaller input conductance, a lower rheobase, and a longer afterhyperpolarization (AHP) than the delayed-firing motoneurons (Leroy et al 2014).…”

“…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). …”