Neurons undergo IFNγ-driven persistent epigenetic shifts and synaptopathy in encephalitis, 2026, Shammas et al

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N_Dina

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

Shammas, Ghazal; Piccinno, Margot; Egervari, Kristof; Lemeille, Sylvain; Mariotte, Alexandre; Maltese, Federica; Panzeri, Alessandra; Wagner, Ingrid; Fonta, Nicolas; Furlan, Tiphaine; Kreutzfeldt, Mario; Vincenti, Ilena; Yermanos, Alexander; Page, Nicolas; Bellone, Camilla; Muñoz, Carmen Picon; Liberto, Giovanni Di; Merkler, Doron

In infectious and autoimmune disorders of the central nervous system, neurons can become cognate immunological targets of cytotoxic T cells, leading to persistent functional and synaptic impairments. However, the molecular underpinnings of such irreversible alterations remain unclear. Using a cytotoxic T cell-driven viral encephalitis mouse model, we found synaptic loss and altered neuronal excitability that outlasted the immune response in chronically diseased mice. Employing conditional reporter mice, bulk RNA sequencing (RNA-seq), single-nucleus RNA sequencing (snRNA-seq), chromatin immunoprecipitation followed by sequencing (ChIP-seq), and assay for transposase-accessible chromatin followed by sequencing (ATAC-seq), we mapped the trajectory of transient and sustained epigenetic shifts and transcriptional changes in neurons. Notably, virus-exposed neurons, as cognate targets of cytotoxic T cells, developed interferon-gamma (IFNγ)-mediated persistent chromatin closing, reducing transcription factor accessibility and downstream synaptic gene expression. Analogous synaptic transcriptional signatures were observed in neurons of human encephalitis. Our study identifies a novel IFNγ-driven neuronal epigenetic adaptation program underlying persistent synaptopathy with implications for chronic neuroinflammatory disorders.

Highlights​

• CD8+ T cell encephalitis triggers neuronal transcriptional and epigenetic shifts
• Persistent chromatin inaccessibility associates with reduced synaptic gene expression
• IFNγ drives non-cytolytic viral clearance, lasting epigenetic changes, and synaptopathy
• Rasmussen patient neurons share transcriptomic changes, supporting a conserved mechanism

Web (Cell) | DOI: 10.1016/j.neuron.2025.11.006
 
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Made a social media summary about this study:



1) Interesting study showing that a brain infection in mice can lead to loss of synapses and altered excitability of neurons that outlasts the immune response against the virus.

Changes are induced by interferon-gamma and involve epigenetic remodelling in the hippocampus.

2) In this experiment, neurons of mice were infected with a virus (non-cytolytic lymphocytic choriomeningitis virus, or LCMV). This created a cytotoxic T-cell response in the brain and a model to study viral encephalitis.

3) The mice got sick and had cognitive impairments but there was no significant neuronal loss. The virus was cleared without destroying cells. The authors did find altered neuronal connectivity and excitability. So the neurons weren't destroyed but they were working differently.

4) The researchers looked at what drove these changes and it seems to be the cytokine interferon-gamma. They found that it induced epigenetic changes that weren't seen in mice with deficient receptors for interferon-gamma (but it likely wasn't the only signal).

5) Interferon-gamma set a cascade in motion, a change in how genes are used or not. Chromatin and synapse-related genes were downregulated. This also happened in bystander neurons that weren't infected and was more strongly the case in the hippocampus than in the brainstem.

6) They found similar changes in hippocampal tissues of humans with a neuroinflammatory condition (Rasmussen encephalitis).

7) This study might be relevant to ME/CFS because in this illness there is a viral trigger of long-term, mostly neurological symptoms but without clear evidence of continued immune activation.

8 ) In addition, genes involved in synaptic plasticity such as Syngap1 that was studied in this mouse experiment have come up in genetic analyses of ME/CFS, such as the recent preprint by the Snyder group at Stanford.
https://www.medrxiv.org/con.../10.1101/2025.04.15.25325899v2
 
V.R.T. said:
I haven't heard of them being tried - i dont know much about them, could you explain their relevance to this paper?
Click to expand...
I know of HDACi and epigenetic changes as in the Post Finasteride Syndrome community (very different presentation than CFS) , where the leading theory is epigenetic changes to 5-alpha reductase expression, specifically over expression.

There was a big push to “reset” epigenetic changes by using a HADCi, specifically valporic acid. Highly frowned upon and for good reason, as the over expression theory has not been proven and valporic acid is a nasty drug. Their white paper and ongoing research should hopefully shed light on this in the future.

HADCi’s allow the chromatin to reopen allowing the reversal of epigenetic silencing. The thing is it affects so much more than this.
 
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Yeah, HDAC inhibitors are in the category of “only worth it if the patient has no other options and is already hurtling towards a painful death.” Some absurdly high percentage of cardiac events, plus the possibility of curing one cancer just to end up with another drug-induced cancer
 
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