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dc.contributor.authorCho, Sukhee
dc.contributor.authorMuthukumar, Allie
dc.contributor.authorStork, Tobias
dc.contributor.authorCoutinho-Budd, Jaeda C.
dc.contributor.authorFreeman, Marc R.
dc.date2022-08-11T08:09:29.000
dc.date.accessioned2022-08-23T16:32:49Z
dc.date.available2022-08-23T16:32:49Z
dc.date.issued2018-10-30
dc.date.submitted2018-12-06
dc.identifier.citation<p>Proc Natl Acad Sci U S A. 2018 Oct 30;115(44):11316-11321. doi: 10.1073/pnas.1800830115. Epub 2018 Oct 16. <a href="https://doi.org/10.1073/pnas.1800830115">Link to article on publisher's site</a></p>
dc.identifier.issn0027-8424 (Linking)
dc.identifier.doi10.1073/pnas.1800830115
dc.identifier.pmid30327343
dc.identifier.urihttp://hdl.handle.net/20.500.14038/37963
dc.description.abstractAstrocytes 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=30327343&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1073/pnas.1800830115
dc.subjectDrosophila
dc.subjectastrocyte
dc.subjectfocal adhesions
dc.subjectglutamate transporters
dc.subjecthyperexcitability
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCells
dc.subjectNervous System
dc.subjectNervous System Diseases
dc.subjectNeuroscience and Neurobiology
dc.titleFocal adhesion molecules regulate astrocyte morphology and glutamate transporters to suppress seizure-like behavior
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume115
dc.source.issue44
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/neurobiology_pp/237
dc.identifier.contextkey13437583
html.description.abstract<p>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.</p>
dc.identifier.submissionpathneurobiology_pp/237
dc.contributor.departmentFreeman Lab
dc.contributor.departmentGraduate School of Biomedical Sciences, Neuroscience Program
dc.contributor.departmentNeurobiology
dc.source.pages11316-11321
dc.contributor.studentAllie K. Muthukumar
dc.contributor.studentSukhee Cho
dc.description.thesisprogramNeuroscience


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