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J Neurosci. 2015 Jan 14;35(2):707-20. doi: 10.1523/JNEUROSCI.1682-14.2015.

Homeostatic dysregulation in membrane properties of masticatory motoneurons compared with oculomotor neurons in a mouse model for amyotrophic lateral sclerosis.

Author information

  • 1Departments of Integrative Biology and Physiology, and.
  • 2Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095.
  • 3Departments of Integrative Biology and Physiology, and schandler@physci.ucla.edu.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative motoneuron disease with presently no cure. Motoneuron (MN) hyperexcitability is commonly observed in ALS and is suggested to be a precursor for excitotoxic cell death. However, it is unknown whether hyperexcitability also occurs in MNs that are resistant to degeneration. Second, it is unclear whether all the MNs within homogeneous motor pools would present similar susceptibility to excitability changes since high-threshold MNs innervating fast fatigable muscle fibers selectively degenerate compared with low-threshold MNs innervating fatigue resistant slow muscle fibers. Therefore, we concurrently examined the excitability of ALS-vulnerable trigeminal motoneurons (TMNs) controlling jaw musculature and ALS-resistant oculomotor neurons (OMNs) controlling eye musculature in a well studied SOD1(G93A) ALS mouse model using in vitro patch-clamp electrophysiology at presymptomatic ages P8-P12. Our results show that hyperexcitability is not a global change among all the MNs, although mutant SOD1 is ubiquitously expressed. Instead, complex changes occur in ALS-vulnerable TMNs based on motor unit type and discharge characteristics. Firing threshold decreases among high-threshold TMNs and increases in a subpopulation of low-threshold TMNs. The latter group was identified based on their linear frequency-current responses to triangular ramp current injections. Such complex changes in MN recruitment were absent in ALS-resistant OMNs. We simulated the observed complex changes in TMN excitability using a computer-based jaw closer motor pool model. Model results suggest that hypoexcitability may indeed represent emerging disease symptomology that causes resistance in muscle force initiation. Identifying the cellular and molecular properties of these hypoexcitable cells may guide effective therapeutic strategies in ALS.

KEYWORDS:

brainstem; excitability; mastication; neurodegeneration; presymtomatic

PMID:
25589764
PMCID:
PMC4293417
DOI:
10.1523/JNEUROSCI.1682-14.2015
[PubMed - indexed for MEDLINE]
Free PMC Article
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