Optogenetic investigation of dynamic Fas signaling network in the adult hippocampus

Abstract

Fas receptor (CD95) is known to lead both cell death and pro-survival outputs and be activated in numerous neurological diseases. Given its complexity, how the Fas signaling pathway operates dynamically has not yet been fully understood. Recent advances in optogenetics enable a thorough investigation of a signaling network which can also explain cellular responses or fates, including the phenomenon observed in various disorders. We here developed chemogenetically and optogenetically activatable Fas modules that operate in a physiologically plausible manner. Activation of Fas in immature neurons in the dentate gyrus induced mTOR activation and subsequent secretion of BDNF. Phosphorylation of Erk in neural stem cells was triggered upon prolonged Fas activation. When repetitively activated, this signaling network resulted in the proliferation of neural stem cells and a transient enhancement of spatial working memory in mice. Our work demonstrates a novel Fas signaling network in the dentate gyrus with optogenetic dissection as well as its consequences regarding adult hippocampal neurogenesis and memory increase.