Region-specific regulation of presynaptic dopamine homeostasis by D 2 autoreceptors shapes the in vivo impact of the neuropsychiatric disease-associated DAT variant val559

Abstract

Disruptionsof dopamine(DA) signaling contribute to abroad spectrum of neuropsy chiatric disorders, includingattention-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 anomalousDAT-mediatedDAefflux(ADE). Here, wedemonstratethat region-specificcontributionsof D 2 autoreceptors(D2AR)topresynaptic 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. Incontrast, theactivity of tyrosinehydrox-ylase(TH)isD2AR-dependent inbothregions. IntheDSbut not VSof Val559mice, tonicactivationof D2ARsdrivesapositivefeedbackloopthat 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.