Neurons undergo IFNγ-driven persistent epigenetic shifts and synaptopathy in encephalitis.

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Neurons can be immunological targets in central nervous system disorders, leading to persistent impairments.
• The molecular mechanisms behind irreversible neuronal alterations remain unclear.

Purpose of the Study:

• To elucidate the molecular underpinnings of persistent synaptic impairments in neurons targeted by cytotoxic T cells.
• To investigate the role of epigenetic modifications in chronic neuroinflammatory disorders.

Main Methods:

• Utilized a viral encephalitis mouse model.
• Employed conditional reporter mice, bulk and single-nucleus RNA sequencing (RNA-seq, snRNA-seq).
• Performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) and ATAC-seq to map epigenetic and transcriptional changes.

Main Results:

• Synaptic loss and altered neuronal excitability persisted beyond the immune response in mice.
• Neurons developed persistent, interferon-gamma (IFNγ)-mediated chromatin closing.
• This epigenetic change reduced transcription factor accessibility and downstream synaptic gene expression, a signature also seen in human encephalitis.

Conclusions:

• Identified a novel IFNγ-driven neuronal epigenetic adaptation program.
• This program underlies persistent synaptopathy (synaptic dysfunction).
• Findings have implications for understanding and treating chronic neuroinflammatory disorders.