Unexpected contribution of striatal projection neurons co-expressing dopamine D1 and D2 receptors in balancing motor control

The prevailing model of the basal ganglia motor control posits that the striatum, the input nucleus fo the basal ganglia, orchestrates the selection of voluntary actions through two circuits, the direct and the indirect pathways that oppose each other in thalamocortical activation. These circuits originate from two different populations of spiny projecting neurons (SPNs) projecting to different output structures and classically distinguished by differential expression of dopamine (DA) D1 receptor- and D2 receptor (D1-SPNs and D2-SPNs), respectively, regardless of SPNs co-expressing these two receptors (D1/D2-SPNs). However, growing evidence indicates several levels of heterogeneity within the striatal system at the molecular level, identifying several clusters of SPNs, but also at the functional level, where activation of both pathways can elicit both excitations and inhibitions in output structures and in the cortex. Here, our goal is to highlight, target and elucidate the function of this third striatal population carrying a dual antagonist dopaminergic signaling and which would underlie, at least in part, these heterogeneous, even opposing responses.