Focal adhesion molecules regulate astrocyte morphology and glutamate transporters to suppress seizure-like behavior
Department of Neurobiology; Graduate School of Biomedical Sciences, Neuroscience Program; Freeman Lab
Amino Acids, Peptides, and Proteins | Cells | Nervous System | Nervous System Diseases | Neuroscience and Neurobiology
Astrocytes are important regulators of neural circuit function and behavior in the healthy and diseased nervous system. We screened for molecules in Drosophila astrocytes that modulate neuronal hyperexcitability and identified multiple components of focal adhesion complexes (FAs). Depletion of astrocytic Tensin, beta-integrin, Talin, focal adhesion kinase (FAK), or matrix metalloproteinase 1 (Mmp1), resulted in enhanced behavioral recovery from genetic or pharmacologically induced seizure. Overexpression of Mmp1, predicted to activate FA signaling, led to a reciprocal enhancement of seizure severity. Blockade of FA-signaling molecules in astrocytes at basal levels of CNS excitability resulted in reduced astrocytic coverage of the synaptic neuropil and expression of the excitatory amino acid transporter EAAT1. However, induction of hyperexcitability after depletion of FA-signaling components resulted in enhanced astrocyte coverage and an approximately twofold increase in EAAT1 levels. Our work identifies FA-signaling molecules as important regulators of astrocyte outgrowth and EAAT1 expression under normal physiological conditions. Paradoxically, in the context of hyperexcitability, this pathway negatively regulates astrocytic process outgrowth and EAAT1 expression, and their blockade leading to enhanced recovery from seizure.
Drosophila, astrocyte, focal adhesions, glutamate transporters, hyperexcitability
DOI of Published Version
Proc Natl Acad Sci U S A. 2018 Oct 30;115(44):11316-11321. doi: 10.1073/pnas.1800830115. Epub 2018 Oct 16. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Cho, Sukhee; Muthukumar, Allie; Stork, Tobias; Coutinho-Budd, Jaeda C.; and Freeman, Marc R., "Focal adhesion molecules regulate astrocyte morphology and glutamate transporters to suppress seizure-like behavior" (2018). Neurobiology Publications and Presentations. 237.