Stra8 links neuronal activity to inhibitory circuit protection in the adult mouse brain.

While neuronal activity is essential for brain function, it also poses threats to neuronal integrity. Here, we show that activity-induced expression of stimulated by retinoic acid gene 8 (Stra8) protects neurons from degeneration. Previously considered germline specific, Stra8 is expressed in the adult mouse brain and is induced by neuronal activity via calcium influx and N-methyl-D-aspartate (NMDA) receptor signaling. Neuron-specific Stra8 knockout mice display hallmark features of neurodegeneration, including DNA damage, impaired proteostasis, inflammation, nuclear envelope erosion, reduced dendritic plasticity, memory deficits, and heightened excitotoxic vulnerability. Electrophysiological studies reveal disrupted inhibitory circuit function. Mechanistically, Stra8 binds regulatory regions of neuromodulator genes and regulates their expression. Notably, Stra8 loss upregulates the expression of Npas4, an immediate-early gene critical for inhibitory circuits, but the aberrant protein is mislocalized to the nuclear periphery. These findings identify Stra8 as an activity-dependent transcriptional regulator that safeguards neuronal structure and function.