By the same logic, one can conclude that alterations in intrinsic excitability of VTA DA neurons are not the primary cause of the DA-dependent phenotypes in Girk2−/− mice. Indeed, ablation of Girk2 but not Girk1 should enhance the intrinsic excitability of VTA DA neurons, particularly if these neurons exhibit a high degree of basal Girk channel activity. While intrinsic excitability of VTA DA neurons may be elevated in Girk2−/− mice, these neurons exhibited lower spontaneous activity ex vivo. Firing rates were normalized by picrotoxin, indicating that VTA DA neurons from Girk2−/− mice receive elevated inhibitory input from local GABA neurons (Sugita et al. 1992). While this elevated inhibitory tone may be offset in vivo by elevated excitatory input (as our data suggest), these data do not support the contention that the DA-dependent hyperactivity in Girk2−/− mice reflects the enhanced intrinsic excitability of VTA DA neurons.
