التفاصيل البيبلوغرافية
| العنوان: |
Region-Specific Regulation of Presynaptic Dopamine Homeostasis by D2 Autoreceptors Shapes the In Vivo Impact of the Neuropsychiatric Disease-Associated DAT Variant Val559. |
| المؤلفون: |
Gowrishankar, Raajaram, Gresch, Paul J., Davis, Gwynne L., Katamish, Rania M., Riele, Justin R., Stewart, Adele M., Vaughan, Roxanne A., Hahn, Maureen K., Blakely, Randy D. |
| المصدر: |
Journal of Neuroscience; 6/6/2018, Vol. 38 Issue 23, p5302-5312, 11p |
| مصطلحات موضوعية: |
NEUROBEHAVIORAL disorders, HOMEOSTASIS, DOPAMINE, AUTORECEPTORS, PATHOLOGICAL psychology |
| مستخلص: |
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 D2 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-dependentinbothregions. In the DS but not VS of Val559 mice, tonic activation ofD2ARsdrivesapositive feedback loop that promotes surface expression of efflux-prone DATs, raising extracellular DA levels and overwhelming DAT-mediated DA clearance capacity. WhereasD2ARsthat regulate DAT are tonically activated in the Val559 DS,D2ARsthat regulate TH become desensitized, allowing maintenance of cytosolic DA needed to sustain ADE. Together with prior findings, our results argue for distinctD2ARpools 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. [ABSTRACT FROM AUTHOR] |
|
Copyright of Journal of Neuroscience is the property of Society for Neuroscience and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
