Dopaminergic Signaling and Locomotor Behaviors are Regulated by Gq-Receptor-Mediated Dopamine Transporter Trafficking and the Parkinson's Risk Allele Rit2
Authors
Kearney, Patrick J.Faculty Advisor
Haley MelikianAcademic Program
NeuroscienceDocument Type
Doctoral DissertationPublication Date
2022-03-18Keywords
DopamineDopamine Transporter
DAT
GPCR
Gq
mGluR5
Rit2
Parkinson's disease
Motor learning
coordination
Behavioral Neurobiology
Biochemistry
Molecular and Cellular Neuroscience
Molecular Biology
Metadata
Show full item recordAbstract
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-rc53Permanent Link to this Item
http://hdl.handle.net/20.500.14038/32396Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/hsp0-rc53