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Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16883-8. doi: 10.1073/pnas.1419497111. Epub 2014 Nov 10.

Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS.

Author information

  • 1Interdepartmental Program in Neuroscience.
  • 2Department of Neurobiology.
  • 3Howard Hughes Medical Institute, Department of Genetics, and.
  • 4Howard Hughes Medical Institute, Department of Genetics, and Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, CT 06510 arthur.horwich@yale.edu david.mccormick@yale.edu.
  • 5Department of Neurobiology, Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, CT 06510 arthur.horwich@yale.edu david.mccormick@yale.edu.

Abstract

Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) affects motor neurons (MNs) in the brain and spinal cord. Understanding the pathophysiology of this condition seems crucial for therapeutic design, yet few electrophysiological studies in actively degenerating animal models have been reported. Here, we report a novel preparation of acute slices from adult mouse spinal cord, allowing visualized whole cell patch-clamp recordings of fluorescent lumbar MN cell bodies from ChAT-eGFP or superoxide dismutase 1-yellow fluorescent protein (SOD1YFP) transgenic animals up to 6 mo of age. We examined 11 intrinsic electrophysiologic properties of adult ChAT-eGFP mouse MNs and classified them into four subtypes based on these parameters. The subtypes could be principally correlated with instantaneous (initial) and steady-state firing rates. We used retrograde tracing using fluorescent dye injected into fast or slow twitch lower extremity muscle with slice recordings from the fluorescent-labeled lumbar MN cell bodies to establish that fast and slow firing MNs are connected with fast and slow twitch muscle, respectively. In a G85R SOD1YFP transgenic mouse model of ALS, which becomes paralyzed by 5-6 mo, where MN cell bodies are fluorescent, enabling the same type of recording from spinal cord tissue slices, we observed that all four MN subtypes were present at 2 mo of age. At 4 mo, by which time substantial neuronal SOD1YFP aggregation and cell loss has occurred and symptoms have developed, one of the fast firing subtypes that innvervates fast twitch muscle was lost. These results begin to describe an order of the pathophysiologic events in ALS.

KEYWORDS:

amyotrophic lateral sclerosis; electrophysiology; motor neurons; neurodegeneration

PMID:
25385594
PMCID:
PMC4250117
DOI:
10.1073/pnas.1419497111
[PubMed - indexed for MEDLINE]
Free PMC Article
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