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

• Published in: Brain (London, England : 1878) Vol. 129; no. 4; pp. 953 - 962
• Main Authors: Kanai, Kazuaki, Kuwabara, Satoshi, Misawa, Sonoko, Tamura, Noriko, Ogawara, Kazue, Nakata, Miho, Sawai, Setsu, Hattori, Takamichi, Bostock, Hugh
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2006; Oxford Publishing Limited (England)
• Subjects: Adult; Aged; Aged, 80 and over; ALS = amyotrophic lateral sclerosis; amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - physiopathology; Axons - physiology; Biological and medical sciences; CMAP = compound muscle action potential; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Progression; Electric Stimulation - methods; fasciculation; Fasciculation - physiopathology; Female; Humans; Male; Medical sciences; Middle Aged; Models, Neurological; Motor Neurons - physiology; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neural Conduction; Neurology; persistent sodium channel; potassium channel; Potassium Channels - physiology; SMA = spinal muscular atrophy; Sodium Channels - physiology; strength-duration time constant; TEd = depolarizing threshold electrotonus; TEh = hyperpolarizing threshold electrotonus; threshold electrotonus; Nervous system diseases; strength-duration time constant; persistent sodium channel; Fasciculation; Excitability; Amyotrophic lateral sclerosis; threshold electrotonus; Sodium; Central nervous system disease; Electrotonus; potassium channel; Degenerative disease; Spinal cord disease; Potassium; Strength
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awl024

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.