Journal article
Region-Specific Regulation of Presynaptic Dopamine Homeostasis by D 2 Autoreceptors Shapes the In Vivo Impact of the Neuropsychiatric Disease-Associated DAT Variant Val559
The Journal of neuroscience, Vol.38(23), pp.5302-5312
06/06/2018
DOI: 10.1523/JNEUROSCI.0055-18.2018
PMCID: PMC5990980
PMID: 29739866
Abstract
Disruptions of dopamine (DA) signaling contribute to a broad spectrum of neuropsychiatric disorders, including attention-deficit hyperactivity disorder (ADHD), addiction, bipolar disorder, and schizophrenia. Despite evidence that risk for these disorders derives from heritable variation in DA-linked genes, a better understanding is needed of the molecular and circuit context through which gene variation drives distinct disease traits. Previously, we identified the DA transporter (DAT) variant Val559 in subjects with ADHD and established that the mutation supports anomalous DAT-mediated DA efflux (ADE). Here, we demonstrate that region-specific contributions of D
autoreceptors (D2AR) to presynaptic DA homeostasis dictate the consequences of Val559 expression in adolescent male mice. We show that activation of D2ARs in the WT dorsal striatum (DS), but not ventral striatum (VS), increases DAT phosphorylation and surface trafficking. In contrast, the activity of tyrosine hydroxylase (TH) is D2AR-dependent in both regions. In the DS but not VS of Val559 mice, tonic activation of D2ARs drives a positive feedback loop that promotes surface expression of efflux-prone DATs, raising extracellular DA levels and overwhelming DAT-mediated DA clearance capacity. Whereas D2ARs that regulate DAT are tonically activated in the Val559 DS, D2ARs that regulate TH become desensitized, allowing maintenance of cytosolic DA needed to sustain ADE. Together with prior findings, our results argue for distinct D2AR pools that regulate DA synthesis versus DA release and inactivation and offer a clear example of how the penetrance of gene variation can be limited to a subset of expression sites based on differences in intersecting regulatory networks.
Altered dopamine (DA) signaling has been linked to multiple neuropsychiatric disorders. In an effort to understand and model disease-associated DAergic disturbances, we previously screened the DA transporter (DAT) in subjects with attention-deficit hyperactivity disorder (ADHD) and identified multiple, functionally impactful, coding variants. One of these variants, Val559, supports anomalous DA efflux (ADE) and in transgenic mice leads to changes in locomotor patterns, psychostimulant sensitivity, and impulsivity. Here, we show that the penetrance of Val559 ADE is dictated by region-specific differences in how presynaptic D
-type autoreceptors (D2ARs) constrain DA signaling, biasing phenotypic effects to dorsal striatal projections. The Val559 model illustrates how the impact of genetic variation underlying neuropsychiatric disorders can be shaped by the differential engagement of synaptic regulatory mechanisms.
Details
- Title: Subtitle
- Region-Specific Regulation of Presynaptic Dopamine Homeostasis by D 2 Autoreceptors Shapes the In Vivo Impact of the Neuropsychiatric Disease-Associated DAT Variant Val559
- Creators
- Raajaram Gowrishankar - Vanderbilt UniversityPaul J Gresch - Florida Atlantic UniversityGwynne L Davis - Vanderbilt UniversityRania M Katamish - Department of Biomedical Science, Charles E. Schmidt College of Medicine, andJustin R Riele - Vanderbilt UniversityAdele M Stewart - Vanderbilt UniversityRoxanne A Vaughan - University of North DakotaMaureen K Hahn - Florida Atlantic UniversityRandy D Blakely - Florida Atlantic University
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.38(23), pp.5302-5312
- DOI
- 10.1523/JNEUROSCI.0055-18.2018
- PMID
- 29739866
- PMCID
- PMC5990980
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Grant note
- R01 MH105094 / NIMH NIH HHS F31 MH107132 / NIMH NIH HHS T32 MH065215 / NIMH NIH HHS
- Language
- English
- Date published
- 06/06/2018
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618513002771
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