Motor neuron firing in a transgenic mouse model of amyotrophic lateral sclerosis: a simulation study

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease selectively affecting motor neurons functioning. Mutations of the Cu,Zn superoxide dismutase (SOD1) account for 20% of the familial cases of ALS. Previous studies investigated spinal motor neurons excitability in transgenic mice overexpressing the mutated (Gly93 → Ala) human SOD1 enzyme and showed that expression of the human G93A-mutant SOD1 gene induces a different excitability in motor neurons with respect to control and SOD1 motor neurons. We developed a mathematical model able to reproduce the firing properties of spinal motor neuron in non-transgenic mice. We performed a sensitivity analysis on the model to identify modifications in conductances and/or kinetics of the ionic currents that can be responsible of the observed alterations both in firing frequency and in AP duration in G93A motor neurons. We found that changes limited to ionic current conductances are not able to reproduce G93A firing alterations. We observed that the mutant motor neuron hyperexcitability can be reproduced by means of a faster kinetic of small conductance calciumdependent potassium current. Thus, we propose this current mutation as a possible mechanism underlying ALS-associated alterations.