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J Physiol. 2014 Apr 1;592(7):1687-703. doi: 10.1113/jphysiol.2013.265843. Epub 2014 Jan 20.

Adult spinal motoneurones are not hyperexcitable in a mouse model of inherited amyotrophic lateral sclerosis.

Author information

1
Laboratoire de Neurophysique et Physiologie, UMR CNRS 8119, Université Paris Descartes, 45 rue des Saints-Pères, 75006 Paris, France. marin.manuel@neurobio.org.

Abstract

In amyotrophic lateral sclerosis (ALS), an adult onset disease in which there is progressive degeneration of motoneurones, it has been suggested that an intrinsic hyperexcitability of motoneurones (i.e. an increase in their firing rates), contributes to excitotoxicity and to disease onset. Here we show that there is no such intrinsic hyperexcitability in spinal motoneurones. Our studies were carried out in an adult mouse model of ALS with a mutated form of superoxide dismutase 1 around the time of the first muscle fibre denervations. We showed that the recruitment current, the voltage threshold for spiking and the frequency-intensity gain in the primary range are all unchanged in most spinal motoneurones, despite an increased input conductance. On its own, increased input conductance would decrease excitability, but the homeostasis for excitability is maintained due to an upregulation of a depolarizing current that is activated just below the spiking threshold. However, this homeostasis failed in a substantial fraction of motoneurones, which became hypoexcitable and unable to produce sustained firing in response to ramps of current. We found similar results both in lumbar motoneurones recorded in anaesthetized mice, and in sacrocaudal motoneurones recorded in vitro, indicating that the lack of hyperexcitability is not caused by anaesthetics. Our results suggest that, if excitotoxicity is indeed a mechanism leading to degeneration in ALS, it is not caused by the intrinsic electrical properties of motoneurones but by extrinsic factors such as excessive synaptic excitation.

PMID:
24445319
PMCID:
PMC3979619
DOI:
10.1113/jphysiol.2013.265843
[Indexed for MEDLINE]
Free PMC Article

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