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    Dopaminergic Signaling and Locomotor Behaviors are Regulated by Gq-Receptor-Mediated Dopamine Transporter Trafficking and the Parkinson's Risk Allele Rit2

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    Name:
    Kearney_Dissertation_Revised.pdf
    Embargo:
    2024-05-04
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    7.738Mb
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    Authors
    Kearney, Patrick J.
    Faculty Advisor
    Haley Melikian
    Academic Program
    Neuroscience
    UMass Chan Affiliations
    Melikian Lab
    Neurobiology
    Document Type
    Doctoral Dissertation
    Publication Date
    2022-03-18
    Keywords
    Dopamine
    Dopamine Transporter
    DAT
    GPCR
    Gq
    mGluR5
    Rit2
    Parkinson's disease
    Motor learning
    coordination
    Behavioral Neurobiology
    Biochemistry
    Molecular and Cellular Neuroscience
    Molecular Biology
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    Abstract
    Dopamine (DA) is a modulatory neurotransmitter required for movement, learning, and reward. Several neuropsychiatric disorders exhibit DAergic dysfunction, including Parkinson’s disease (PD). The presynaptic DA transporter (DAT) constrains DAergic signaling via DA reuptake. Acute PKC activation drives DAT endocytosis, however, endogenous receptor-mediated DAT trafficking in striatal terminals remains ill-defined. Here, I present data supporting biphasic Gq-receptor-mediated DAT trafficking in striatum. Gq-receptor activation drives initial DAT insertion, which requires DA release, DAergic DRD2auto activation, and intact retromer. Subsequent DAT retrieval requires PKC and the neuronal GTPase Rit2. Furthermore, I demonstrate that the endogenous Gq-coupled metabotropic glutamate receptor, mGluR5, expressed on DAergic neurons exerts biphasic DAT regulation. DAergic mGluR5 silencing revealed that mGluR5 is required for motor learning and coordination. DAergic mGluR5 cKO motor deficits were rescued by DAT inhibition, suggesting mGluR5-mediated DAT trafficking is required for these behaviors. Apart from its requisite role in DAT trafficking, Rit2 is a PD associated risk allele. We previously demonstrated that Rit2 is required for psychostimulant response and generalized anxiety, but not basal locomotion. However, Rit2’s roles in more complex motor behaviors and PD pathology remain unknown. DAergic Rit2 silencing revealed that Rit2 is required for male motor learning and prolonged Rit2 suppression leads to progressive manifestation of PD biomarkers, coordination deficits, and decreased DAergic tone. Motor learning deficits were rescued by boosting DA availability, echoing Rit2-mediated hypodopaminergia. Together these results identify receptor-mediated DAT trafficking mechanisms in DA terminals, demonstrate that DAT surface dynamics are required for motor function, and implicate DAergic Rit2 loss in progressive PD-like phenotypes.
    DOI
    10.13028/hsp0-rc53
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32396
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/hsp0-rc53
    Scopus Count
    Collections
    Neurobiology Student Publications
    Morningside GSBS Dissertations and Theses

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