The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death

SUMMARY Inhibitory interneurons integrate into developing circuits in specific ratios and distributions. In the cortex, the formation of inhibitory networks occurs concurrently with the apoptotic elimination of a third of GABAergic interneurons. The molecular mechanisms that select GABAergic interneurons to survive or die are unknown. Here we report that the clustered Protocadherins regulate GABAergic cell survival in the developing brain. Deletion of the Pcdh-gamma genes (Pcdhgs) from GABAergic neurons in mice causes a severe loss of inhibitory neurons in multiple brain regions and results in motor deficits and seizure activities. By focusing on the neocortex and cerebellar cortex, we demonstrate that GABAergic interneuron loss results from elevated apoptosis during the postnatal wave of Bax- dependent programmed cell death. Pro-survival AKT signals are reduced in Pcdhg- deficient interneurons, diminishing the intrinsic capacity of interneurons to compete and incorporate into developing networks. We propose that the Pcdhgs mediate selective GABAergic interneuron survival to contribute to the formation of balanced inhibitory networks.