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Title page for ETD etd-06062018-103704


Type of Document Dissertation
Author Gowrishankar, Raajaram
URN etd-06062018-103704
Title Modeling Molecular And Physiological Contributions To Dopamine-Associated Neuropsychiatric Disorders
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
Danny G. Winder Committee Chair
Brad A. Grueter Committee Member
Eugenia V. Gurevich Committee Member
Randy D. Blakely Committee Member
Keywords
  • dopamine D2 autoreceptor
  • neuropsychiatric disorders
  • dopamine transporter
  • dopamine
Date of Defense 2018-05-10
Availability unrestricted
Abstract
Genetic and imaging studies implicate disrupted DA availability in multiple psychiatric disorders, yet how variation in DA-linked genes leads to disease is unclear. Dopamine (DA) neurotransmission is controlled by the D2 autoreceptor (D2AR), which inhibits vesicular DA release, and the DA transporter (DAT) that clears synaptic DA, thereby terminating DA signaling. Further control is imposed by the D2AR-enhancement of DAT surface levels and subsequently activity, and via the inhibition of DA synthesis. The need to model DA perturbations with translational validity led to DAT Val559, found in ADHD, ASD and BPD. DAT Val559 mice display altered locomotion, motivation and impulsivity, behavioral traits that align well with symptoms found in subjects the variant was isolated from. Molecularly, DAT Val559 triggers DAT reversal, leading to anomalous DA efflux (ADE), which was to cause elevated extracellular DA levels in the striatum, resulting in constitutive D2AR-driven reductions in vesicular DA release. Furthermore, D2AR regulation of DAT is functionally uncoupled in DA axons to the ventral striatum, but D2AR control of DA neurotransmission is not, biasing the penetrance of DAT Val559 to dorsal striatum-selective DA axons. DAT Val559 thus engenders tonic D2AR activity, sustaining ADE that can be blocked by acute D2AR antagonism, thereby disrupting patterned neural activity and imposing a state of functional hyperdopaminergia, selectively in the dorsal striatum. Our studies provide novel insights into how broadly expressed genetic variation can sculpt heterogeneity in clinical symptoms, now widely recognized in the DSM-V, through inherent diversity in DA signaling mechanisms.
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