Neural precursors (NPCs) from adult L967Q mice display early commitment to "in vitro" neuronal differentiation and...

The pathogenic factors leading to selective degeneration of motoneurons in ALS are not yet understood. However, altered functionality of voltage-dependent Na(+) channels may play a role since cortical hyperexcitability was described in ALS patients and riluzole, the only drug approved to treat ALS, seems to decrease glutamate release via blockade or inactivation of voltage-dependent Na(+) channels. The wobbler mouse, a murine model of motoneuron degeneration, shares some of the clinical features of human ALS. At early stages of the wobbler disease, increased cortical hyperexcitability was observed. Moreover, riluzole reduced motoneuron loss and muscular atrophy in treated wobbler mice. Here, we focussed our attention on specific electrophysiological properties, like voltage-activated Na(+) currents and underlying regenerative electrical activity, as read-outs of the neuronal maturation process of neural stem/progenitor cells (NPCs) isolated from the subventricular zone (SVZ) of adult early symptomatic wobbler mice. In self-renewal conditions, the rate of wobbler NPC proliferation "in vitro" was 30% lower than that of healthy mice. Conversely, the number of wobbler NPCs displaying early neuronal commitment and action potentials was significantly higher. Upon switching from proliferative to differentiative conditions, NPCs underwent significant changes in the key properties of voltage gated Na(+) currents. The most notable finding, in cells with neuronal morphology, was an increase in Na(+) current density that strictly correlated with an increased probability to generate action potentials. This feature was remarkably more pronounced in neurons differentiated from wobbler NPCs that upon sustained stimulation, displayed short trains of pathological facilitation. In agreement with this result, an increase in the number of c-Fos positive cells, a surrogate marker of neuronal network activation, was observed in the mesial cortex of the wobbler mice "in situ". Thus these findings, all together, suggest that a state of early neuronal hyperexcitability may be a major contributor of motoneuron vulnerability.