The Electrophysiological Determinants of Corticospinal Motor Neuron Vulnerability in ALS

Javier H. Jara, Patrick L. Sheets, Maximiliano José Nigro, Mina Perić, Carolyn Brooks, Daniel B. Heller, Marco Martina, Pavle R. Andjus, P. Hande Ozdinler*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

The brain is complex and heterogeneous. Even though numerous independent studies indicate cortical hyperexcitability as a potential contributor to amyotrophic lateral sclerosis (ALS) pathology, the mechanisms that are responsible for upper motor neuron (UMN) vulnerability remain elusive. To reveal the electrophysiological determinants of corticospinal motor neuron (CSMN, a.k.a UMN in mice) vulnerability, we investigated the motor cortex of hSOD1G93A mice at P30 (postnatal day 30), a presymptomatic time point. Glutamate uncaging by laser scanning photostimulation (LSPS) revealed altered dynamics especially within the inhibitory circuitry and more specifically in L2/3 of the motor cortex, whereas the excitatory microcircuits were unchanged. Observed microcircuitry changes were specific to CSMN in the motor column. Electrophysiological evaluation of the intrinsic properties in response to the microcircuit changes, as well as the exon microarray expression profiles of CSMN isolated from hSOD1G93A and healthy mice at P30, revealed the presence of a very dynamic set of events, ultimately directed to establish, maintain and retain the balance at this early stage. Also, the expression profile of key voltage-gated potassium and sodium channel subunits as well as of the inhibitory GABA receptor subunits and modulatory proteins began to suggest the challenges CSMN face at this early age. Since neurodegeneration is initiated when neurons can no longer maintain balance, the complex cellular events that occur at this critical time point help reveal how CSMN try to cope with the challenges of disease manifestation. This information is critically important for the proper modulation of UMNs and for developing effective treatment strategies.

Original languageEnglish (US)
Article number73
JournalFrontiers in Molecular Neuroscience
Volume13
DOIs
StatePublished - May 19 2020

Keywords

  • amyotrophic lateral sclerosis
  • corticospinal motor neurons
  • hereditary spastic paraplegia
  • microcircuit
  • neuronal vulnerability
  • primary lateral sclerosis
  • upper motor neurons

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'The Electrophysiological Determinants of Corticospinal Motor Neuron Vulnerability in ALS'. Together they form a unique fingerprint.

  • Cite this