Focal adhesion molecules regulate astrocyte morphology and glutamate transporters to suppress seizure-like behavior

Sukhee Cho, Allie K. Muthukumar, Wilm Tobias Stork, Jaeda C. Coutinho-Budd, Marc Freeman

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)11316-11321
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number44
DOIs
StatePublished - Oct 30 2018

Fingerprint

Amino Acid Transport System X-AG
Focal Adhesions
Astrocytes
Seizures
Matrix Metalloproteinase 1
Talin
Behavioral Genetics
Amino Acid Transport Systems
Focal Adhesion Protein-Tyrosine Kinases
Excitatory Amino Acids
Neuropil
Nervous System Diseases
Integrins
Drosophila

Keywords

  • Astrocyte
  • Drosophila
  • Focal adhesions
  • Glutamate transporters
  • Hyperexcitability

ASJC Scopus subject areas

  • General

Cite this

Focal adhesion molecules regulate astrocyte morphology and glutamate transporters to suppress seizure-like behavior. / Cho, Sukhee; Muthukumar, Allie K.; Stork, Wilm Tobias; Coutinho-Budd, Jaeda C.; Freeman, Marc.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 44, 30.10.2018, p. 11316-11321.

Research output: Contribution to journalArticle

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