Stra8, an Activity-Dependent Modulator of Neural Circuit, Safeguards Neuronal Integrity

While neuronal activity is essential for brain function, it inherently threatens neurons and impairs neuronal integrity1. Here we show that activity-induced expression of Stra8 (stimulated by retinoic acid gene 8) plays a crucial role in protecting neuronal integrity. To date, Stra8 has been considered as germline-specific2, and its role in somatic cells has not been explored. Our results show that Stra8 is expressed in the adult mouse brain. Neuronal activity (i.e., exploration of a novel environment) induced Stra8 expression, and this process is mediated by calcium influx and depolarization through NMDA-type glutamate receptors. Importantly, neuron-specific knockout of Stra8 induced multifaceted features of neuronal degeneration in young adult mice, including accumulation of DNA damage, impaired proteostasis, heightened inflammation, nuclear membrane erosion, decreased dendritic plasticity, as well as impaired learning and memory and increased vulnerability to kainic acid-induced excitotoxicity. Additionally, electrophysiology studies show that loss of Stra8 compromises inhibitory neural circuity and function. Mechanistically, Stra8 binds to the regulatory sequences of neuromodulator genes and regulates their expression, among which loss of Stra8 results in an upregulated expression of Npas4; however, aberrantly expressed Npas4 protein is confined to the nuclear periphery in neurons. Together, these findings establish Stra8 as an activity-dependent modulator of neural circuitry that protects neuronal integrity.