TY - JOUR
T1 - Focal adhesion molecules regulate astrocyte morphology and glutamate transporters to suppress seizure-like behavior
AU - Cho, Sukhee
AU - Muthukumar, Allie K.
AU - Stork, Tobias
AU - Coutinho-Budd, Jaeda C.
AU - Freeman, Marc R.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank all members of the M.R.F. laboratory for helpful discussions; the Vienna Drosophila RNAi Center; the TRiP at Harvard Medical School; and the Bloomington Stock Center for providing fly stocks. For the EAAT1 antibody, we thank Dr. Don J. van Meyel. We also thank the University of Massachusetts Medical School Electron Microscopy core facility, especially Dr. L. Strittmatter, for technical assistance with TEM experiments. EM study was supported by Award S10RR027897 from the National Center for Research Resources. This work was supported by National Institute of Neurological Disorders and Stroke Grant R01NS053538 (to M.R.F.).
PY - 2018/10/30
Y1 - 2018/10/30
N2 - 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, β-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.
AB - 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, β-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.
KW - Astrocyte
KW - Drosophila
KW - Focal adhesions
KW - Glutamate transporters
KW - Hyperexcitability
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U2 - 10.1073/pnas.1800830115
DO - 10.1073/pnas.1800830115
M3 - Article
C2 - 30327343
AN - SCOPUS:85055626341
VL - 115
SP - 11316
EP - 11321
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 44
ER -