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

Aberrant dopamine (DA) signalling 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 the 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), which 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 signalling and behaviour differently in males and females. Our studies reveal the ability of the construct‐valid DAT Val559 model to elucidate endogenous mechanisms that support DA signalling, findings that may be of translational and/or therapeutic importance.