Alterations of electrical properties in the adult motoneurons in the mSOD1 mouse model of Amyotrophic Lateral Sclerosis

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In Amyotrophic Lateral Sclerosis (ALS), spinal motoneurons degenerate in the order of large motoneurons that innervate fast and fatigable muscle fibers to small motoneurons that innervate slow muscle fibers (Pun et al. 2006). This order of degeneration is peculiar in that it is in direct opposition to the normal order of motorneuron recruitment, where small motoneurons are recruited first, followed by larger motoneurons (Henneman et al. 1965b). This difference in vulnerability of motoneurons depending on size and muscle type is also interesting because the intrinsic excitability of these motoneurons differ; small motoneurons are more excitable than larger motoneurons as the latter require much more amount of input to be able to bring to threshold. Recent discovery of changes in the size and intrinsic excitability of motoneurons in ALS, as early as embryonic through neonatal states (Kuo et al. 2004; Kuo et al. 2005; Martin et al. 2013; Quinlan et al. 2011; van Zundert et al. 2008; Leroy et al 2014) to adult states (Delestree et al. 2014), motivated this thesis work; begging the question, exactly what happens to the excitability of motoneurons, particularly in the persistent inward currents, as animals progress through ALS? Persistent inward currents (PICs), a mixture of sodium and calcium currents, can profoundly influence the output of motoneurons by changing the threshold to fire as well as the rate of firing. The absence of PICs can lead to motoneurons not able to fire repetitively at all (Kuo et al. 2006b), while presence of PICs can lead to motoneurons that continue to fire even in the absence of synaptic input (Heckman 2003). We found that these strong currents were upregulated in the SOD1 mouse model of ALS in the early adult state, possibly to compensate for the huge increase in motoneuron size. As the disease progressed, however, both the size and PICs decreased to the levels not found in wild-type animals. This suggests that hyperexcitable motoneurons that were also abnormally large in size begin to degenerate, interestingly around the time of axonal detachment (Pun et al. 2006). Considering the only FDA-approved therapeutic for ALS (Riluzole) blocks sodium PICs, the results from this study may provide insight into a novel administration regimen to better control the changes of motoneuron excitability in ALS patients

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  • 04/16/2018
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