Faculty AdvisorMarc R. Freeman
Document TypeDoctoral Dissertation
Medicine and Health Sciences
Molecular and Cellular Neuroscience
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AbstractAstrocytes 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.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/32344
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