Numerical Simulation Of Motor Neuron
Excitability In A Transgenic Mouse Model Of
Familial Amyotrophic Lateral Sclerosis
Author(s)
N. Marzocchi, S. Severi, M. Pieri, C. Zona & S. Cavalcanti
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized
by the selective degeneration of motor neurons. Mutations of the Cu,Zn
superoxide dismutase (SOD1) account for 20% of the familial cases of ALS.
Transgenic mice overexpressing the mutated human SOD1 enzyme develop
phenotypic and pathological symptoms resembling ALS in humans. Previous
studies showed that, in this transgenic model of ALS, expression of the human
G93A-mutant SOD1 gene does not affect passive membrane properties, whereas
it induces a different excitability with respect to control and SOD1 motor
neurons. To investigate which modifications at the ionic current level can
produce the observed phenomenon, we developed a numerical simulator of the
electrical activity of mouse spinal motor neuron. The simulator was based on a
mathematical model including a Hodgkin-Huxley (HH)-type parallel
conductance membrane model and a lumped fluid compartment model
accounting for the activity of a cytosolic calcium-binding buffer. The equations
describing voltage-dependent fast sodium current (INa) were modified from a
conventional Hodgkin-Huxley formulation, and the parameters were adjusted in
order to fit experimental data from non-transgenic mouse motor neurons. We
then introduced minimal changes to other model parameters in order to match
available SOD1 current-clamp electrophysiological data. The model is able to
reproduce AP waveform properties as well as the relation between firing
frequency and injected current measured in SOD1 motor neurons. This model
offers a powerful investigative tool, making it possible to identify the current
modifications which could produce the observed effects on G93A motor neurons
excitability.
Keywords: biological system modeling, motor neuron, firing properties,
Hodgkin-Huxley models, ALS.
Keywords
biological system modeling, motor neuron, firing properties,
Hodgkin-Huxley models, ALS.
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