Dissertations, Theses, and Capstone Projects

Date of Degree

2-2020

Document Type

Dissertation

Degree Name

Ph.D.

Program

Psychology

Advisor

Itzhak Mano

Committee Members

Christine Li

Jonathan Levitt

Ratna Sircar

Jeremy Dittman

Hannes Büelow

Subject Categories

Molecular and Cellular Neuroscience | Molecular Genetics

Keywords

Excitotoxicity, Neurodegeneration, Neuroprotection, Glutamate receptor, Insulin; Insulin‐like growth factor (IGF), Signaling; FoxO, Caenorhabditis elegans (C. elegans), Tamalin/GRAS-1

Abstract

Brain ischemia is a major cause of debilitation and death in the United States. Excitotoxicity, a condition that arises from the accumulation of glutamate (Glu) in the synapse that leads to overactivation of Glu receptors (GluRs), is the major mechanism of neuronal damage in brain ischemia / stroke. Although it is commonly acknowledged that over activation of GluRs leads to neurodegeneration, it has been recently shown that even during excitotoxicity Glu has a concurrent important role in regulating neuroprotection. GluR-activated transcription factors seem to mediate this neuroprotection, but it remains unclear which signaling cascades and transcription factors are regulated by GluRs in excitotoxicity. The Insulin/IGF signaling (IIS) cascade is intensely studied for its role in regulating longevity and cell stress resistance. Using C. elegans as a model, we have previously shown that the IIS cascade also regulates neuroprotection in excitotoxicity in the nematode via its role in regulating transcription factor DAF-16. However, a link between GluRs and the IIS cascade has not been fully investigated. We suggest that GluRs may regulate the IIS cascade via complex formation at the postsynaptic density. Here we identify the scaffolding protein Tamalin/GRAS-1 as a functional bridge linking the communication between GluRs and IIS. We found Tamalin/GRAS-1 to be important in regulating neuroprotection by working cell autonomously via the IIS cascade. We also show that there is a physical link between GluRs and upstream regulation of the IIS cascade whose activity is controlled by Tamalin/GRAS-1. These studies suggest a novel conduit of communication between Glu and insulin signaling to regulate susceptibility to excitotoxic neurodegeneration.

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