Identification of Synaptotagmin 10 as Effector of NPAS4-Mediated Protection from Excitotoxic Neurodegeneration

Abstract

Aberrant synaptic activity is observed in many neurological disorders and has been suggested as an important factor contributing to the pathophysiology. Intriguingly, pathophysiologic activity can also trigger signaling cascades mediating potentially compensatory neuroprotection against excitotoxic insult. Here, we identify a new neuroprotective signaling cascade involving the activity-induced transcriptional regulator NPAS4 and the vesicular Ca(2+)-sensor protein synaptotagmin 10 (Syt10). Syt10 is required for NPAS4 to protect hippocampal neurons against excitotoxic cell death. NPAS4 in turn controls the activity of the Syt10 gene, which is strongly induced by pathophysiologic activity. Our results uncover an entirely unexpected, novel function of Syt10 underlying the response of neurons to pathophysiologic activity and provide new therapeutic perspectives for neurological disorders.