Neuronal STAT1 as a phase switch from antiviral defense to synaptopathy in encephalitis

Abstract

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.

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BibTeX RIS

BibTeX

@article{liberto2026neuronal,
  title = {{Neuronal STAT1 as a phase switch from antiviral defense to synaptopathy in encephalitis}},
  author = {Giovanni Di Liberto and Doron Merkler},
  journal = {Trends in Neurosciences},
  year = {2026},
  month = oct,
  doi = {10.1016/j.tins.2026.04.007},
  url = {https://hal.science/hal-05793135v1},
  note = {CC BY},
}

RIS

TY  - JOUR
TI  - Neuronal STAT1 as a phase switch from antiviral defense to synaptopathy in encephalitis
AU  - Giovanni Di Liberto
AU  - Doron Merkler
PY  - 2026
DA  - 2026/10/11
JO  - Trends in Neurosciences
DO  - 10.1016/j.tins.2026.04.007
UR  - https://hal.science/hal-05793135v1
AB  - 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.
SN  - 0166-2236
SN  - 1878-108X
ER  -

Abstract

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