Interferon signaling is essential for antiviral defense in the central nervous system, yet sustained neuronal STAT1 phosphorylation (pSTAT1) can promote immune-mediated synaptic and network injury. In this opinion article, we argue that neuronal pSTAT1 functions as a context-dependent switch across viral and autoimmune encephalitis, shifting from antiviral protection to durable synaptopathy and excitability changes when interferon signaling persists. Integrating mechanistic, epigenomic, and translational evidence from mouse models and human neuropathology, we propose that prolonged neuronal pSTAT1 drives a durable synaptopathic program by silencing synaptic gene networks and epigenetic 'locking' of dysfunctional circuits. We discuss therapeutic opportunities and risks of targeting the JAK-STAT1 axis, emphasizing the trade-off between neuroprotection and antiviral immunity.
Liberto et al. (Fri,) studied this question.