RT Journal Article SR Electronic T1 The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmental cell death JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP JN-RM-1636-20 DO 10.1523/JNEUROSCI.1636-20.2020 A1 Candace H. Carriere A1 Wendy Xueyi Wang A1 Anson D. Sing A1 Adam Fekete A1 Brian E. Jones A1 Yohan Yee A1 Jacob Ellegood A1 Harinad Maganti A1 Lola Awofala A1 Julie Marocha A1 Amar Aziz A1 Lu-Yang Wang A1 Jason P. Lerch A1 Julie L. Lefebvre YR 2020 UL http://www.jneurosci.org/content/early/2020/10/09/JNEUROSCI.1636-20.2020.abstract AB Inhibitory interneurons integrate into developing circuits in specific ratios and distributions. In the neocortex, inhibitory network formation occurs concurrently with the apoptotic elimination of a third of GABAergic interneurons. The cell surface molecules that select interneurons to survive or die are unknown. Here, we report that members of the clustered Protocadherins (cPCDHs) control GABAergic interneuron survival during developmentally-regulated cell death. Conditional deletion of the gene cluster encoding the gamma-Protocadherins (Pcdhgs) from developing GABAergic neurons in mice of either sex causes a severe loss of inhibitory populations in multiple brain regions and results in neurological deficits such as seizures. By focusing on the neocortex and the cerebellar cortex, we demonstrate that reductions of inhibitory interneurons result from elevated apoptosis during the critical postnatal period of programmed cell death. By contrast, cortical interneuron populations are not affected by removal of Pcdhgs from pyramidal neurons or glial cells. Interneuron loss correlates with reduced AKT signaling in Pcdhg mutant interneurons, and is rescued by genetic blockade of the pro-apoptotic factor BAX. Together, these findings identify the PCDHGs as pro-survival transmembrane proteins that select inhibitory interneurons for survival and modulate the extent of programmed cell death. We propose that the PCDHGs contribute to the formation of balanced inhibitory networks by controlling the size of GABAergic interneuron populations in the developing brain.SIGNIFICANCE STATEMENTA pivotal step for establishing appropriate excitatory-inhibitory ratios is adjustment of neuronal populations by cell death. In the mouse neocortex, a third of GABAergic interneurons are eliminated by BAX-dependent apoptosis during the first postnatal week. Interneuron cell death is modulated by neural activity and pro-survival pathways but the cell-surface molecules that select interneurons for survival or death are unknown. We demonstrate that members of the cadherin superfamily, the clustered gamma-Protocadherins (PCDHGs), regulate the survival of inhibitory interneurons and the balance of cell death. Deletion of the Pcdhgs in mice causes inhibitory interneuron loss in the cortex and cerebellum, and leads to motor deficits and seizures. Our findings provide a molecular basis for controlling inhibitory interneuron population size during circuit formation.