To investigate the function of natively expressed SNX27 in vivo and overcome the obstacle of severe developmental defects, we created a mouse mutant that lacks SNX27 protein in only DA neurons. VTA DA neurons exclusively express GIRK2c and GIRK3 subunits, which contain the PDZ-binding motif required for interacting with SNX27 (Cruz et al., 2004; Lunn et al., 2007). We hypothesized that SNX27 will be required for GIRK function in the VTA DA neurons. We discovered that SNX27 is an essential regulator of GABABR-activated GIRK signaling in VTA DA neurons and helps mitigate the stimulatory effects of cocaine, implicating SNX27 as a promising therapeutic target for treating addiction.
