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Author Notes:

Correspondence: Cassie S. Mitchell cassie.mitchell@bme.gatech.edu

KJ: data collection, statistical analysis, results interpretation, drafting of initial manuscript, critical review of content; JM: data collection, results interpretation, critical review of content; AS: data collection, statistical analysis, critical review of content; CM: framing of study, project oversight, results interpretation, drafting of final manuscript, critical review of content.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Research Funding:

Financial support provided by National Institute of Health grant NS069616, NS081426, and NS098228 to CM.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • glutamate
  • GABA
  • GLT-1
  • ChAT
  • VGF
  • TNF alpha
  • aspartate
  • G93A MICE

Astrocyte-Mediated Neuromodulatory Regulation in Preclinical ALS: A Metadata Analysis


Journal Title:

Frontiers in Cellular Neuroscience


Volume 12


, Pages 491-491

Type of Work:

Article | Final Publisher PDF


Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by progressive degradation of motoneurons in the central nervous system (CNS). Astrocytes are key regulators for inflammation and neuromodulatory signaling, both of which contribute to ALS. The study goal was to ascertain potential temporal changes in astrocyte-mediated neuromodulatory regulation with transgenic ALS model progression: glutamate, GTL-1, GluR1, GluR2, GABA, ChAT activity, VGF, TNFα, aspartate, and IGF-1. We examine neuromodulatory changes in data aggregates from 42 peer-reviewed studies derived from transgenic ALS mixed cell cultures (neurons + astrocytes). For each corresponding experimental time point, the ratio of transgenic to wild type (WT) was found for each compound. ANOVA and a student's t-test were performed to compare disease stages (early, post-onset, and end stage). Glutamate in transgenic SOD1-G93A mixed cell cultures does not change over time (p > 0.05). GLT-1 levels were found to be decreased 23% over WT but only at end-stage (p < 0.05). Glutamate receptors (GluR1, GluR2) in SOD1-G93A were not substantially different from WT, although SOD1-G93A GluR1 decreased by 21% from post-onset to end-stage (p < 0.05). ChAT activity was insignificantly decreased. VGF is decreased throughout ALS (p < 0.05). Aspartate is elevated by 25% in SOD1-G93A but only during end-stage (p < 0.05). TNFα is increased by a dramatic 362% (p < 0.05). Furthermore, principal component analysis identified TNFα as contributing to 55% of the data variance in the first component. Thus, TNFα, which modulates astrocyte regulation via multiple pathways, could be a strategic treatment target. Overall results suggest changes in neuromodulator levels are subtle in SOD1-G93A ALS mixed cell cultures. If excitotoxicity is present as is often presumed, it could be due to ALS cells being more sensitive to small changes in neuromodulation. Hence, seemingly unsubstantial or oscillatory changes in neuromodulators could wreak havoc in ALS cells, resulting in failed microenvironment homeostasis whereby both hyperexcitability and hypoexcitability can coexist. Future work is needed to examine local, spatiotemporal neuromodulatory homeostasis and assess its functional impact in ALS.

Copyright information:

© 2018 Jordan, Murphy, Singh and Mitchell.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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