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Front. Cell. Neurosci. | doi: 10.3389/fncel.2018.00491

Astrocyte-mediated neuromodulatory regulation in preclinical ALS: a metadata analysis

Kathleen Jordan1, Joseph Murphy1, Anjanya Singh1, 2 and  Cassie S. Mitchell1, 3*
  • 1Biomedical Engineering, College of Engineering, Georgia Institute of Technology, United States
  • 2School of Medicine, University of Texas Southwestern Medical Center, United States
  • 3Biomedical Engineering, Emory University School of Medicine, United States

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, TNF, 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). TNF is increased by a dramatic 362% (p<0.05). Furthermore, principal component analysis identified TNF as contributing to 55% of the data variance in the first component. Thus, TNF, 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.

Keywords: Glutamate, Calcium, GLT-1, GluR, Chat, VGF, tNF-alpha, IGF-1

Received: 15 Jan 2018; Accepted: 29 Nov 2018.

Edited by:

Margaret S. Ho, ShanghaiTech University, China

Reviewed by:

Erik B. Malarkey, Vertex Pharmaceuticals (United States), United States
Manoj K. Gottipati, Rensselaer Polytechnic Institute, United States
Yu-Feng Wang, Harbin Medical University, China  

Copyright: © 2018 Jordan, Murphy, Singh and Mitchell. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Cassie S. Mitchell, PH.D.., College of Engineering, Georgia Institute of Technology, Biomedical Engineering, Atlanta, 30332, GA, United States,