Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Abstract

Fast axonal conduction of action potentials in mammals relies on myelin insulation. Demyelination can cause slowed, blocked, desynchronized, or paradoxically excessive spiking that underlies the symptoms observed in demyelination diseases. The diversity and timing of such symptoms are poorly understood, often intermittent, and uncorrelated with disease progress. We modeled the effects of demyelination (and secondary remodeling) on intrinsic axonal excitability using Hodgkin-Huxley and reduced Morris-Lecar models. Simulations and analysis suggested a simple explanation for the breadth of symptoms and revealed that the ratio of sodium to leak conductance, g Na /g L , acted as a four-way switch controlling excitability patterns that included spike failure, single spike transmission, afterdischarge, and spontaneous spiking. Failure occurred when this ratio fell below a threshold value. Afterdischarge occurred at g Na /g L just below the threshold for spontaneous spiking and required a slow inward current that allowed for two stable attractor states, one corresponding to quiescence and the other to repetitive spiking. A neuron prone to afterdischarge could function normally unless it was switched to its "pathological" attractor state; thus, although the underlying pathology may develop slowly by continuous changes in membrane conductances, a discontinuous change in axonal excitability can occur and lead to paroxysmal symptoms. We conclude that tonic and paroxysmal positive symptoms as well as negative symptoms may be a consequence of varying degrees of imbalance between g Na and g L after demyelination. The KCNK family of g L potassium channels may be an important target for new drugs to treat the symptoms of demyelination. O ligodendrocytes and Schwann cells tightly wrap axons at regular intervals to form the myelin sheath that allows for rapid axonal conduction. Neuropathies involving axonal demyelination are characterized by the unraveling of this insulation and can affect both the central nervous system, as in the case of multiple sclerosis (MS), and the peripheral nervous system, as in Guillain-Barré syndrome.Causes of demyelination include immunologic disease processes, as well as lesions such as traumatic nerve damage, nonpenetrating spinal cord injuries, and chronic nerve compression (1-4). Regardless of the precise etiology, clinical presentation often involves negative (loss-of-function) symptoms, including loss of motor control (i.e., paresis) and sensory deficits such as blindness and numbness, as well as positive (gain-of-function) symptoms, including muscle spasms, tactile allodynia, and chronic pain that is constant or paroxysmal (1, 4-7). Which muscles or sensory modalities are affected depends on where in the nervous system the demyelinating lesions develop, but changes in conduction velocity alone are clearly insufficient to explain the breadth of symptoms observed, especially the positive ones. In particular, MS often produces confounding symptoms that can present intermittently, resolving and retu...

A computational model coupling mechanics and electrophysiology in spinal cord injury

“…This includes aspects of AP propagation, such as a deeper study of unstable saltatory behaviors in damaged myelinated axons (Boucher et al 2012) or in demyelinated axon (Waxman and Brill 1978;Coggan et al 2010) and their relation to mechanical loading.…”

Cooperativity between remote sites of ectopic spiking allows afterdischarge to be initiated and maintained at different locations

“…The internodes nonetheless allowed for the longitudinal spread of both ions and current. Parameter values, ion densities and distributions (soma: g Na = 80, g K = 790, g L = 3, g NaP = 0.19; node or neuroma: g Na = 1500, g K = 1600, g L = 70, g NaP = 1.9, all in mS/cm 2 ) were the same as previously reported (Coggan et al 2010), except when otherwise indicated.…”

“…Our HH model (previously described in (Coggan et al 2010, 2011) included a soma (15 µm), axon hillock (8 µm, with 4:1 mm taper), initial segment (10 µm), and a linear set of 80 pairs of myelinated internodes (200 µm each) and nodes of Ranvier (1 µm each). Results were not qualitatively altered by including a T-junction and central axon branch to the end of the initial segment so as to more accurately capture primary afferent morphology.…”

“…Results were not qualitatively altered by including a T-junction and central axon branch to the end of the initial segment so as to more accurately capture primary afferent morphology. A hyperexcitable, 10 µm-long unmyelinated region referred to as the “neuroma” was inserted at the midpoint of the axon (Coggan et al 2010, 2011). Axon diameter throughout was 1 µm unless otherwise stated.…”

“…2002; see Coggan et al 2010, 2011 for details) is described by the following equations. $$I_{\mathit{\text{NaP}}}=g_{\mathit{\text{NaP}}}{m_p}^{3}false(V_m-E_{\mathit{\text{Na}}}false),$$ $$\frac{{\mathit{\text{dm}}}_p}{\mathit{\text{dt}}}=false[{\alpha }_{m}false(1-mfalse)-{\beta }_{m}mfalse],$$ $${\alpha }_P=A_{\alpha }false(V_m+B_{\alpha }false)/false(1-e^{false[-false(V_m+B_{\alpha }false)/C_{\alpha }false]}false),$$ $${\beta }_P=A_{\beta }false[-false(V_m+B_{\beta }false)false]/false(1-e^{false[-false(V_m+B_{\beta }false)/C_{\beta }false]}false),$$ Parameters had the following base values: for α P , A α =0.01, B α =27 mV and C α = 10.2 mV; and for β P , A β =0.000251, B β =34 mV and C β = 10 mV.…”