GSBS Dissertations and Theses

ORCID ID

0000-0002-2553-6296

Approval Date

12-14-2017

Document Type

Doctoral Dissertation

Academic Program

Neuroscience

Department

Neurobiology; Freeman Lab

First Thesis Advisor

Marc R. Freeman

Keywords

astrocyte, morphology, electron microscopy, Drosophila, genetics, seizure, focal adhesions, tensin, integrin, glutamate transporters

Abstract

Astrocytes are emerging as important regulators of neural circuit function and behavior in the healthy and diseased nervous system. In a screen for astrocyte molecules that modulate neuronal hyperexcitability we identified multiple components of focal adhesion complexes (FAs) as potent suppressors of genetically- or pharmacologically-induced seizure-like activity. Depletion of astrocytic Tensin, b-integrin, Talin, Focal adhesion kinase (FAK), or matrix metalloproteinase 1 (Mmp1), which degrades extracellular matrix to activate b-integrin receptors, resulted in enhanced recovery from, or resistance to seizure activity. Reciprocally, promoting FA signaling by overexpression of Mmp1 in astrocytes led to enhanced-seizure severity. Blockade of FA signaling in astrocytes led to reduced-astrocytic coverage of the synaptic neuropil and reduced expression of the excitatory amino acid transporter EAAT1. However, upon seizure induction, depletion of FA signaling components resulted in enhanced astrocyte coverage of the synaptic neuropil and a ~2-fold increase in EAAT1 levels compared to controls. Our data indicate that FAs promote astrocyte coverage in neuropil and EAAT1 expression under normal physiological conditions, but in the context of hyperexcitability, FAs negatively regulate the extent of astrocytic processes within neuropil and EAAT1 expression, thereby inhibiting a more rapid recovery from conditions of excessive neuronal activity.

DOI

10.13028/M2Q100

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Copyright is held by the author, with all rights reserved.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Saturday, September 08, 2018

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