Martínez-Silva ML, Imhoff-Manuel RD, Sharma A, Heckman CJ, Shneider NA, Roselli F, Zytnicki D, Manuel M. Hypoexcitability precedes denervation in the large fast-contracting motor units in two unrelated mouse models of ALS. Elife. 2018 Mar 27;7 PubMed.
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Boston Children's Hospital
The data presented in the paper are compelling. In the two mouse models of ALS studied, reduced repetitive firing is present selectively in those motor neurons most vulnerable to degeneration, an interesting and potentially important observation.
However, although the authors argue that hypoexcitability contributes to the degeneration of motor neurons in ALS, this is not demonstrated—they have only shown a correlation/association, not a causal link. If they had shown that an intervention that increases repetitive firing rescued the motor neuron from cell death, or that in healthy controls, reducing repetitive firing caused cell death, then one could reasonably infer that the decreased repetitive firing phenotype was mechanistically related to susceptibility to cell death.
Interestingly, they find in both of the mouse ALS models the vulnerable motor neurons had more depolarized membrane potentials. One could argue this reflects hyperexcitability, in that voltage-dependent phenomena would now be recruited, including possibly more calcium influx, which could contribute to neurotoxicity. I would argue their data shows evidence then, of abnormal excitability rather than just of hypo- or hyperexcitability, and this is compatible with the seemingly contradictory literature.
The big issue is how this relates to the altered excitability present in ALS patients, where increased excitability is argued from several studies to be a poor prognostic sign. Does this mean the animal models are not true surrogates of the human disease or that the human observations are incorrect? A further issue is whether these changes in excitability are compensatory reactions by diseased neurons or are drivers of the disease. As mentioned by the authors hyperexcitability may occur early followed later by hypoexcitability—which of these contributes to degeneration and how, and when should we intervene to abort this and with what kind of therapy? These are all important questions that this excellent study raises, and the challenge now is to find the answers. ALS is a complex disease and it is likely that the mechanisms responsible are complex, too.
View all comments by Clifford WoolfMotor neuronal hyperexcitability potentially contributes to motor neuron death in amyotrophic lateral sclerosis (ALS). Many previous studies support this hypothesis, including clinical trials of riluzole, a glutamate antagonist that delays ALS progression (Miller et al., 2012). Here, the researchers examined motor neuronal excitability, utilizing SOD1 and FUS mice, and demonstrated that hypoexcitability is an early sign of degeneration in fast fatigable (FF) and fast fatigue-resistant (FR) motor neuron somas and precedes motor neuron degeneration.
However, previous neurophysiological studies, utilizing threshold tracking transcranial magnetic stimulation and nerve excitability measurements, and other methods disclosed that motor neuronal hyperexcitability is an early sign in ALS patients (Vucic et al., 2008; Iwai et al., 2016). How can we interpret this discrepancy? Recently, non-cell autonomous pathways have drawn many researchers’ attention. Alterations in such pathways may occur also in the preclinical stage (Eisen et al., 2014). A recent study revealed that GABAergic dysfunction contributes to ALS progression (Shibuya et al., 2016). It is notable that not only leading actors, i.e., motor neurons, but also supporting actors, such as inhibitory interneurons, axons, neuromuscular junctions, astrocytes, microglia, and others, may contribute to motor neuron hyperexcitability and are worth further study to understand ALS pathogenesis and overcome this disease. Edaravone, a free radical scavenger, was found helpful for ALS and was approved in Japan and by the U.S. FDA, and emphasizes the importance of this viewpoint.
References:
Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012 Mar 14;3:CD001447. PubMed.
Vucic S, Nicholson GA, Kiernan MC. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain. 2008 Jun;131(Pt 6):1540-50. Epub 2008 May 9 PubMed.
Iwai Y, Shibuya K, Misawa S, Sekiguchi Y, Watanabe K, Amino H, Kuwabara S. Axonal Dysfunction Precedes Motor Neuronal Death in Amyotrophic Lateral Sclerosis. PLoS One. 2016;11(7):e0158596. Epub 2016 Jul 6 PubMed.
Eisen A, Kiernan M, Mitsumoto H, Swash M. Amyotrophic lateral sclerosis: a long preclinical period?. J Neurol Neurosurg Psychiatry. 2014 Mar 19; PubMed.
Shibuya K, Park SB, Geevasinga N, Menon P, Howells J, Simon NG, Huynh W, Noto Y, Götz J, Kril JJ, Ittner LM, Hodges J, Halliday G, Vucic S, Kiernan MC. Motor cortical function determines prognosis in sporadic ALS. Neurology. 2016 Aug 2;87(5):513-20. Epub 2016 Jul 8 PubMed.
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