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 language | English (US) |
|---|---|
| Pages (from-to) | 11316-11321 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 115 |
| Issue number | 44 |
| DOIs | |
| State | Published - Oct 30 2018 |
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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 journal › Article
}
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, Wilm Tobias
AU - Coutinho-Budd, Jaeda C.
AU - Freeman, Marc
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
UR - http://www.scopus.com/inward/record.url?scp=85055626341&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055626341&partnerID=8YFLogxK
U2 - 10.1073/pnas.1800830115
DO - 10.1073/pnas.1800830115
M3 - Article
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 -