Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage.

Fasciculations are a characteristic feature of amyotrophic lateral sclerosis (ALS), and can arise proximally or distally in the motor neuron, indicating a widespread disturbance in membrane excitability. Previous studies of axonal excitability properties (i.e. threshold electrotonus, strength-duration time constant) have suggested respectively that change in potassium or sodium channels may be involved. To reinvestigate these changes and explore their correlation with disease stage, multiple axonal excitability properties (threshold electrotonus, strength-duration time constant, recovery cycle and current-threshold relationship) were measured for the median nerve at the wrist in 58 ALS patients, and compared with 25 age-matched controls. In ALS, there were greater changes in depolarizing threshold electrotonus (i.e. less accommodation) (P < 0.001) and greater supernormality in the recovery cycles (P < 0.001). These abnormalities were more prominent in patients with moderately reduced CMAP (1-5 mV). Modelling the excitability changes in this group supported the hypothesis that axonal potassium conductances are reduced, resulting in increased supernormality despite membrane depolarization. The tendency for strength-duration time constant to be prolonged in ALS was only significant for patients with normal CMAP amplitude (>5 mV). Patients with severely reduced CMAP (<1 mV) alone showed reduced threshold changes to hyperpolarizing current. These results suggest a changing pattern of abnormal membrane properties with disease progression. First, persistent Na+ conductance increases, possibly associated with collateral sprouting, and then K(+) conductances decline. Both changes cause axonal hyperexcitability, and may contribute to the generation of fasciculations. These serial changes in axonal properties could provide insights into the pathophysiology of ALS, and implications for future therapeutic options.

[1]  Jean-Pierre Julien,et al.  Efficient three‐drug cocktail for disease induced by mutant superoxide dismutase , 2003, Annals of neurology.

[2]  R. Willison,et al.  The distribution and frequency of spontaneous fasciculations in motor neurone disease. , 1973, Journal of the neurological sciences.

[3]  Kamilla Angelo,et al.  Pharmacological modulation of SK3 channels , 2001, Neuropharmacology.

[4]  K. Yagui,et al.  The acute effects of glycemic control on axonal excitability in human diabetics , 2004, Annals of neurology.

[5]  B. Brooks,et al.  El escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis , 1994, Journal of the Neurological Sciences.

[6]  L. Xu,et al.  Neuroprotective agent riluzole dramatically slows inactivation of Kv1.4 potassium channels by a voltage-dependent oxidative mechanism. , 2001, The Journal of pharmacology and experimental therapeutics.

[7]  H. Bostock,et al.  Effects of membrane polarization and ischaemia on the excitability properties of human motor axons. , 2000, Brain : a journal of neurology.

[8]  D. Burke,et al.  Threshold tracking techniques in the study of human peripheral nerve , 1998, Muscle & nerve.

[9]  C. Heckman,et al.  Increased persistent Na+ current and its effect on excitability in motoneurones cultured from mutant SOD1 mice , 2005, The Journal of physiology.

[10]  D. Burke,et al.  Strength-duration properties of sensory and motor axons in amyotrophic lateral sclerosis. , 1998, Brain : a journal of neurology.

[11]  H Bostock,et al.  Axonal ion channel dysfunction in amyotrophic lateral sclerosis. , 1995, Brain : a journal of neurology.

[12]  J. Rekling.  Neuroprotective effects of anticonvulsants in rat hippocampal slice cultures exposed to oxygen/glucose deprivation , 2003, Neuroscience Letters.

[13]  K. Morrison.  Therapies in amyotrophic lateral sclerosis-beyond riluzole. , 2002, Current opinion in pharmacology.

[14]  D. Burke,et al.  Differences in membrane properties of axonal and demyelinating Guillain‐Barré syndromes , 2002, Annals of neurology.

[15]  E. Schon,et al.  Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients , 2002, Journal of neurochemistry.

[16]  F. A. Seiler,et al.  Numerical Recipes in C: The Art of Scientific Computing , 1989 .

[17]  D. Burke,et al.  Multiple measures of axonal excitability: A new approach in clinical testing , 2000, Muscle & nerve.

[18]  R. Layzer.  The origin of muscle fasciculations and cramps , 1994, Muscle & nerve.

[19]  P. Leigh,et al.  Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. , 1996, Lancet.

[20]  G. Sobue,et al.  Gene expression profile of spinal motor neurons in sporadic amyotrophic lateral sclerosis , 2005, Annals of neurology.

[21]  P. Grafe,et al.  Abnormal axonal inward rectification in diabetic neuropathy , 1996, Muscle & nerve.

[22]  P. Jonas,et al.  ATP-sensitive and Ca-activated K channels in vertebrate axons: novel links between metabolism and excitability , 1991, Pflügers Archiv.

[23]  D. Burke,et al.  Acute tetrodotoxin‐induced neurotoxicity after ingestion of puffer fish , 2005, Annals of neurology.

[24]  S. Scherer,et al.  KCNQ2 Is a Nodal K+ Channel , 2004, The Journal of Neuroscience.

[25]  D. Burke,et al.  Excitability properties of median and peroneal motor axons , 2000, Muscle & nerve.

[26]  David Burke,et al.  Excitability of human axons , 2002 .

[27]  J. Mitchell,et al.  Activation of the Insular Cortex During Dynamic Exercise in Humans , 1997, The Journal of physiology.

[28]  A. Urbani,et al.  Riluzole inhibits the persistent sodium current in mammalian CNS neurons , 2000, The European journal of neuroscience.

[29]  D. Howland,et al.  Disruption of Dynein/Dynactin Inhibits Axonal Transport in Motor Neurons Causing Late-Onset Progressive Degeneration , 2002, Neuron.

[30]  P. Jonas,et al.  A TEA-insensitive flickering potassium channel active around the resting potential in myelinated nerve , 1992, The Journal of Membrane Biology.

[31]  M. Swash,et al.  Fasciculation potentials: A study of amyotrophic lateral sclerosis and other neurogenic disorders , 1998, Muscle & nerve.

[32]  M. Baker.  Axonal flip-flops and oscillators , 2000, Trends in Neurosciences.

[33]  H Bostock,et al.  Effects of temperature on the excitability properties of human motor axons. , 2001, Brain : a journal of neurology.

[34]  I. Forsythe,et al.  Presynaptic Rat Kv1.2 Channels Suppress Synaptic Terminal Hyperexcitability Following Action Potential Invasion , 2003, The Journal of physiology.

[35]  Hugh Bostock,et al.  Action potentials and membrane currents in the human node of Ranvier , 1995, Pflügers Archiv.

[36]  G. Hu,et al.  Targeting Ischemic Stroke with a Novel Opener of ATP-Sensitive Potassium Channels in the Brain , 2004, Molecular Pharmacology.

[37]  Andrew Eisen,et al.  Clinical neurophysiology of motor neuron diseases , 2004 .

[38]  J. Rothwell,et al.  Latent addition in motor and sensory fibres of human peripheral nerve. , 1997, The Journal of physiology.

[39]  M. Kiernan,et al.  Excitability properties of motor axons in patients with spontaneous motor unit activity , 2001, Journal of neurology, neurosurgery, and psychiatry.

[40]  N. Murray,et al.  Evidence for axonal membrane hyperpolarization in multifocal motor neuropathy with conduction block. , 2002, Brain : a journal of neurology.

[41]  F. Mauguière,et al.  Handbook of clinical neurophysiology , 2003 .

[42]  Hugh Bostock,et al.  Variations in excitability of single human motor axons, related to stochastic properties of nodal sodium channels , 2004, The Journal of physiology.

[43]  S. Kuwabara,et al.  Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment. , 2003, Brain : a journal of neurology.

[44]  M. Gurney,et al.  The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies , 1997, Journal of the Neurological Sciences.

[45]  P. Jonas,et al.  Na(+)‐activated K+ channels localized in the nodal region of myelinated axons of Xenopus. , 1994, The Journal of physiology.

[46]  A. Harvey,et al.  Effects of the potassium channel blocking dendrotoxins on acetylcholine release and motor nerve terminal activity , 1988, British journal of pharmacology.

[47]  A. Wickenden.  Potassium channels as anti-epileptic drug targets , 2002, Neuropharmacology.

[48]  H Bostock,et al.  Changes in excitability of human motor axons underlying post‐ischaemic fasciculations: evidence for two stable states. , 1991, The Journal of physiology.

[49]  P. Leigh,et al.  Dose-ranging study of riluzole in amyotrophic lateral sclerosis , 1996, The Lancet.

[50]  William H. Press,et al.  The Art of Scientific Computing Second Edition , 1998 .

[51]  A. Charles,et al.  Riluzole inhibits spontaneous Ca2+ signaling in neuroendocrine cells by activation of K+ channels and inhibition of Na+ channels , 2003, British journal of pharmacology.

[52]  L. Rowland,et al.  Amyotrophic Lateral Sclerosis , 1980, Neurology.