Leaky lessons learned: Efflux prone dopamine transporter variant DAT Val559 reveals sex and circuit specific contributions of D2 receptor signaling to neuropsychiatric disease.

Aberrant dopamine (DA) signaling has been implicated in various neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia, bipolar disorder (BPD) and addiction. The availability of extracellular DA is sculpted by exocytotic release of vesicular DA and subsequent transporter-mediated clearance, rendering the presynaptic DA transporter (DAT) a crucial regulator of DA neurotransmission. D2-type DA autoreceptors (D2ARs) regulate multiple aspects of DA homeostasis, including i) DA synthesis, ii) vesicular release, iii) DA neuron firing, and iv), the surface expression of DAT and DAT- mediated DA clearance. The DAT Val559 variant, identified in boys with ADHD or ASD, as well as in a girl with BPD, supports anomalous DA efflux (ADE), that we have shown drives tonic activation of D2ARs. Through ex vivo and in vivo studies of the DAT Val559 variant using transgenic knock-in mice, we have uncovered a circuit and sex-specific capacity of D2ARs to regulate DAT, which consequently disrupts DA signaling and behavior differently in males and females. Our studies reveal the ability of the construct valid DAT Val559 model to elucidate endogenous mechanisms that support DA signaling, findings that may be of translational and/or therapeutic importance.