Title

TAAR1-dependent astrocyte dysregulation during HAND and METH exposure

Date of Award

12-18-2018

Degree Type

Thesis

Degree Name

Master of Science

Department

Graduate School of Biomedical Sciences

First Advisor

Anuja Ghorpade

Second Advisor

Raghu R. Krishnamoorthy

Third Advisor

Alakananda Basu

Abstract

Excitatory amino-acid transporter (EAAT)-2 is predominantly expressed in astrocytes and clears glutamate from tripartite synapses preventing excitotoxicity. EAAT-2 dysregulation occurs during human immunodeficiency virus (HIV)-associated neuroinflammation and methamphetamine (METH) abuse, leading to neurotoxic outcomes. Trace amine associated receptor (TAAR) 1, a METH receptor in astrocytes, triggers EAAT-2 dysfunction. Protein kinase C (PKC) signaling promotes ubiquitination of EAAT-2 C-terminal lysine residues, resulting in EAAT-2 internalization. As a G protein coupled receptor, TAAR1’s signaling is implicated in PKC activation. In this work, we investigated the role of TAAR1 in PKC-mediated EAAT-2 ubiquitination during HIV-associated neurocognitive disorders (HAND) and METH comorbidities. We evaluated a TAAR1 overexpression model in primary astrocytes to elucidate TAAR1-mediated functional changes. We found that TAAR1-selective inhibitor, EPPTB, reduced EAAT-2 ubiquitination, and a PKC activator decreased glutamate clearance in METH-pretreated human astrocytes. Therapies targeting astrocyte dysfunction may improve outcomes during HAND, METH abuse and other neuroinflammatory disorders.

Comments

Shannon Mythen, TAAR1-dependent astrocyte dysregulation during HAND and METH exposure, Master of Science (Biomedical Sciences), September, 2018, 63 pp., 2 tables, 8 illustrations, bibliography, 67 titles. Available worldwide December 2019.

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