New Metrics of Intrinsic Axonal Excitability from a Computational Model of Demyelination

Abstract

In white matter, oligodendrocytes tightly wrap axons at regular intervals to form the myelin sheath, the primary attribute of which is conduction velocity acceleration. Axonal demyelination diseases represent a devastating group of neurological disorders that affect more than 2 million people annually worldwide. The process of unraveling the periodic insulation causes axon conduction dysfunction in many diseases of the central nervous system (CNS), as in multiple sclerosis (MS) and infectious encephalomyelitis, or the peripheral nervous system (PNS) as in Guillain-Barre or Charcot-Marie-Tooth syndromes. Although the etiology of these diseases in most cases is thought to be immunological, the mechanisms of the diverse neurological symptoms are just as poorly understood. These confounding symptoms can present intermittently, resolving and returning in a way that is desynchronized from re-myelination. Symptoms include spasticity, dysfunction of somatic sensation, motor control, impairment of vision and other modalities. But these multiple neuropathies cannot be understood by conduction velocity changes alone. Physiological features are accompanied by anatomical and cellular perturbations in affected neurons that include changes in voltage-gated ion channel densities.Here we present a compartmental model of a partially demyelinated axon using the NEURON simulator (http://www.neuron.yale.edu/neuron/) that sheds light on the function of normal, healthy axons as well as those undergoing demyelination. The model suggests a simple set of rules that could explain the wide range of intermittent symptoms observed during demyelination. The rules that govern these destabilized excitability patterns are critically dependent on ion channel densities and the anatomical parameters of the axon. Support: HHMI, NIH R01-MH079076.