What is the subcellular mechanism underlying reduced GABABR-activated GIRK currents in DA neurons lacking SNX27? One possibility is that SNX27 alters the maturation of DA neurons and subsequent GIRK expression, since SNX27 has been shown to be important during neurodevelopment (Cai et al., 2011; Kajii et al., 2003). This scenario seems unlikely since ectopic expression of SNX27 in DA neurons of SNX27DA KO mice completely restored GABABR-GIRK currents to wild-type levels. Furthermore, basic electrical properties and fast inhibitory synaptic inputs were unaltered in VTA DA neurons lacking SNX27. Another explanation is that loss of SNX27 affected other signaling proteins that indirectly altered GIRK expression. For example, SNX27 interacts with glutamate receptors (Cai et al., 2011; Wang et al., 2013), 5-HT receptors (Joubert et al., 2004) and β2 adrenergic receptors (Lauffer et al., 2010). However, expressing GIRK2a in VTA DA neurons restored GABABR-GIRK currents to wild-type levels, indicating that the essential proteins needed for GABABR-activated GIRK signaling are present once GIRK channels are expressed on the plasma membrane. The simplest explanation for the reduced GABABR-activated GIRK currents is that fewer GIRK
