The γ-Protocadherins Regulate the Survival of GABAergic Interneurons during Developmental Cell Death

• Published in: The Journal of neuroscience 2020-11, Vol.40 (45), p.8652-8668
• Main Authors: Carriere, Candace H, Wang, Wendy Xueyi, Sing, Anson D, Fekete, Adam, Jones, Brian E, Yee, Yohan, Ellegood, Jacob, Maganti, Harinad, Awofala, Lola, Marocha, Julie, Aziz, Amar, Wang, Lu-Yang, Lerch, Jason P, Lefebvre, Julie L
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; Apoptosis; Apoptosis - genetics; BAX protein; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - physiology; Brain; Cadherins; Cadherins - genetics; Cadherins - physiology; Cell death; Cell Death - physiology; Cell surface; Cell survival; Cerebellum; Cerebral cortex; Cerebral Cortex - cytology; Cerebral Cortex - diagnostic imaging; Cerebral Cortex - growth & development; Circuits; Clonal deletion; Electroencephalography; Female; gamma-Aminobutyric Acid - physiology; Gene deletion; Glial cells; Interneurons; Interneurons - physiology; Magnetic Resonance Imaging; Male; Membrane Potentials - physiology; Membrane proteins; Mice; Mice, Inbred C57BL; Mortality; Neocortex; Nerve Net - physiology; Nervous System Diseases - etiology; Network formation; Neuronal-glial interactions; Neurons; Oncogene Protein v-akt - genetics; Oncogene Protein v-akt - physiology; Population number; Populations; Pyramidal cells; Seizures; Seizures - etiology; Survival; γ-Aminobutyric acid
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1636-20.2020

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 γ-Protocadherins from developing GABAergic neurons in mice of either sex causes a severe loss of inhibitory populations in multiple brain regions and results in neurologic 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 (PCD). By contrast, cortical interneuron (cIN) populations are not affected by removal of from pyramidal neurons or glial cells. Interneuron loss correlates with reduced AKT signaling in 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 PCD. 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. A 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 γ-Protocadherins (PCDHGs), regulate the survival of inhibitory interneurons and the balance of cell death. Deletion of the 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.