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

Unlabelled: Neuronal degeneration represents a pathogenetic hallmark after different brain insults, such as ischemia and status epilepticus (SE). Excessive release of glutamate triggered by pathophysiologic synaptic activity has been put forward as key mechanism in this context. In response to pathophysiologic synaptic activity, multiple signaling cascades are activated that ultimately initiate expression of specific sets of genes, which may decide between neuronal survival versus death. Recently, a core set of genes ["activity-regulated inhibitor of death" (AID) genes] including the transcription factor (TF) NPAS4 (neuronal PAS domain protein 4) has been found to provide activity-induced protection against neuronal death caused by excitotoxic stimulation. However, the downstream targets of AID action mediating neuroprotection remained so far unknown. Here, we have identified synaptotagmin 10 (Syt10), a vesicular Ca(2+) sensor, as the first neuroprotective effector protein downstream of the TF NPAS4. The expression of Syt10 is strongly upregulated by pathophysiologic synaptic activity after kainic acid (KA) exposure and its absence renders mouse hippocampal neurons highly susceptible to excitotoxic insults. We found NPAS4 as critical for the increase in Syt10 levels and in turn the ability of NPAS4 to confer neuroprotection against KA-induced excitotoxicity to be severely diminished in Syt10 knock-out neurons. In summary, our results point to an important role for signaling of the NPAS4-Syt10 pathway in the neuronal response to strong synaptic activity as a consequence of excitotoxic insults.

Significance Statement: 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.