FIGURE 1.

Potential IFN-γ/STAT1 Signaling Mechanisms in Neurons. The exact mechanisms of IFN-γ/STAT1 signaling in neurons are unknown. In canonical IFN-γ/STAT1 signaling, IFN-γ binds the IFNGR, causing JAK1/2 to recruit and phosphorylate STAT1. STAT1 then disassociates from the IFNGR complex and translocates to the nucleus as a homodimer, where it can regulate transcription of ISGs. Neurons do upregulate ISGs in response to IFN-γ in a STAT1-dependent manner. However, the timing and kinetics of STAT1 activation differ from other cells, suggesting neurons may utilize non-canonical signaling mechanisms. The existence of non-canonical IFN-γ/STAT1 has been understudied, especially in neurons. Non-canonical signaling includes intracellular roles for IFN-γ, translocation of the entire IFN-γ/IFNGR1/JAK1/2/STAT1 complex to the nucleus, and non-transcriptional roles for STAT1 in the cytoplasm. STAT1 activation in neurons is delayed and extended, but it is unclear how or why this occurs. Though it has not been studied, we speculate that activation of the IFN-γ/STAT1 pathway in neurons at different subcellular locations may result in different outcomes, especially if activation occurs at a distal site such as on axons or dendrites versus on the soma. IFN-γ/STAT1 signaling also regulates neural activity, which occurs on the timescale of minutes, and JAK2/STAT1 activation regulates the elimination of specifically inactive axons and synapses. In these scenarios, we speculate that IFN-γ/STAT1 may utilize non-canonical mechanisms, which may allow for rapid and site-specific action. Non-transcriptional roles for cytoplasmic STAT1 could facilitate local effects at the synapse via direct interaction of STAT1 with neurotransmitter receptors, like GABAR and AMPAR, and/or other intermediates like PKC which have been implicated in IFN-γ-regulated neural activity