Activity Regulates Cell Death within Cortical Interneurons through a Calcineurin-Dependent Mechanism

Abstract

Summary We demonstrate that cortical interneurons derived from ventral eminences, including the caudal ganglionic eminence, undergo programmed cell death. Moreover, with the exception of VIP interneurons, this occurs in a manner that is activity-dependent. In addition, we demonstrate that, within interneurons, Calcineurin, a calcium-dependent protein phosphatase, plays a critical role in sequentially linking activity to maturation (E15–P5) and survival (P5–P20). Specifically, embryonic inactivation of Calcineurin results in a failure of interneurons to morphologically mature and prevents them from undergoing apoptosis. By contrast, early postnatal inactivation of Calcineurin increases apoptosis. We conclude that Calcineurin serves a dual role of promoting first the differentiation of interneurons and, subsequently, their survival.

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

“…However, cIN number is not affected by manipulations of TrkB or BDNF (Priya et al, 2018;Sanchez-Huertas and Rico, 2011;Southwell et al, 2012), suggesting the regulation of cIN survival by other mechanisms. Neural activity is one critical factor that influences the extent of inhibitory and excitatory PCD in the cortex by modulating pro-survival pathways such as PI3K/Akt and calcineurin/NFAT (Hardingham et al, 2002;Priya et al, 2018;Wagner-Golbs and Luhmann, 2012;Wong et al, 2018), and suppressing pro-apoptotic effectors (Golbs et al, 2011;Heck et al, 2008;Leveille et al, 2010). Blocking cIN activity by NMDA antagonists or chemogenetic approaches accentuates cIN apoptotic loss while depolarization increases the number of surviving cells (Denaxa et al, 2018;Priya et al, 2018;Wang et al, 2017).…”

“…In mice, 30-40% of prospective neocortical GABAergic interneurons are eliminated between postnatal days 5 and 10 (Southwell et al, 2012). Cortical interneuron (cIN) apoptosis occurs through the Baxdependent intrinsic pathway and affects the major classes deriving from the medial and caudal ganglionic eminences (MGE and CGE, respectively) (Denaxa et al, 2018;Priya et al, 2018;Southwell et al, 2012;Wong et al, 2018). cIN PCD occurs on the heels of pyramidal PCD which tapers by P5 (Blanquie et al, 2017;Miller, 1995;Verney et al, 2000;Wong et al, 2018).…”

“…Matching between cINs and pyramidal neurons might be determined by competition for target-derived neurotrophic factors, as in the peripheral nervous system (Dekkers et al, 2013;Deppmann et al, 2008;Snider, 1994). However, cIN number is not affected by manipulations of TrkB or BDNF (Priya et al, 2018;Sanchez-Huertas and Rico, 2011;Southwell et al, 2012), suggesting the regulation of cIN survival by other mechanisms. Neural activity is one critical factor that influences the extent of inhibitory and excitatory PCD in the cortex by modulating pro-survival pathways such as PI3K/Akt and calcineurin/NFAT (Hardingham et al, 2002;Priya et al, 2018;Wagner-Golbs and Luhmann, 2012;Wong et al, 2018), and suppressing pro-apoptotic effectors (Golbs et al, 2011;Heck et al, 2008;Leveille et al, 2010).…”

“…Neural activity is one critical factor that influences the extent of inhibitory and excitatory PCD in the cortex by modulating pro-survival pathways such as PI3K/Akt and calcineurin/NFAT (Hardingham et al, 2002;Priya et al, 2018;Wagner-Golbs and Luhmann, 2012;Wong et al, 2018), and suppressing pro-apoptotic effectors (Golbs et al, 2011;Heck et al, 2008;Leveille et al, 2010). Blocking cIN activity by NMDA antagonists or chemogenetic approaches accentuates cIN apoptotic loss while depolarization increases the number of surviving cells (Denaxa et al, 2018;Priya et al, 2018;Wang et al, 2017). Moreover, increasing the activity of pyramidal neurons or simply their numbers are sufficient to expand the cIN population (Wong et al, 2018).…”

“…Moreover, increasing the activity of pyramidal neurons or simply their numbers are sufficient to expand the cIN population (Wong et al, 2018). However, the influence of activity is cIN class-specific (Priya et al, 2018), and cell-or population-intrinsic factors also contribute to cIN survival (Southwell et al, 2012). Thus, life-or-death decisions among developing GABAergic interneurons are regulated by multiple selective interactions but the molecules that mediate them are unknown.…”