Hypothesis

Chronic type I interferon signaling in the meningeal lymphatic endothelium locks microglia into a epigenetically trained state that preferentially tags weakly active synapses for complement‑mediated removal, thereby driving an over‑consolidation of cortical maps that manifests as age‑related cognitive rigidity.

Mechanistic Basis

Aged meningeal lymphatics exhibit elevated IFN-beta production and sustained JAK-STAT1 activation (1). This cytokine milieu diffuses into the perivascular space and primes microglia via paracrine STAT1 phosphorylation. Persistent STAT1 signaling recruits the H3K9me3 demethylase KDM4D to enhancers of phagocytic genes (e.g., C1qa, C3, Trem2), resulting in a trained‑immunity epigenetic signature characterized by loss of repressive H3K9me3 and gain of H3K4me1 (2). The epigenetically reprogrammed microglia display lowered thresholds for complement tagging of synapses that have experienced sub‑threshold calcium influx, shifting the synaptic plasticity bias toward LTD via increased calcineurin activity and reduced ERK1/2 signaling (3). Concomitantly, neuronal IFN-alpha/beta exposure induces transient SOCS1 up‑regulation, causing JAK‑STAT tachyphylaxis that attenuates BDNF‑TrkB downstream MAPK/ERK signaling, further raising the LTP threshold. The net effect is a selective pruning of weakly activated synapses while strongly co‑active ensembles become over‑represented, producing map over‑consolidation and reduced capacity for novel learning.

Predictions & Tests

1. In aged mice, pharmacological blockade of IFNAR1 with antagonistic antibody will reduce microglial H3K9me3 loss at complement gene enhancers, normalize C1q deposition, and rescue LTP in hippocampal slices measured by field EPSP slope.
2. Conditional deletion of KDM4D in microglia (Cx3cr1-CreER; Kdm4d^fl/fl) will prevent the interferon‑driven shift toward LTD without affecting basal surveillance, and will improve performance on reversal learning tasks but not on reference memory.
3. Administration of a JAK1/2 inhibitor (ruxolitinib) to aged mice for two weeks will lower microglial TNFα/IL‑1β production, decrease synaptic complement tagging (quantified by immunostaining for C3b), and increase behavioral flexibility in a set‑shifting assay.
4. Conversely, chronic low‑dose IFN-beta infusion into the meningeal space of young mice will recapitulate the aged microglial epigenetic signature and induce premature map rigidity, detectable as reduced place‑field remapping in hippocampal calcium imaging during novel environment exposure.

Potential Implications

If validated, this framework redefines cognitive aging as a tunable immune‑synaptic set point rather than irreversible neurodegeneration. It suggests that intermittent modulation of meningeal interferon signaling or microglial epigenetic enzymes could restore cognitive flexibility without requiring global neurogenesis or synaptic overhaul. Moreover, it provides a mechanistic link between systemic interferonopathies and early‑onset cognitive rigidity, opening therapeutic avenues for conditions such as lupus cerebritis or chronic viral infections where type I interferon is persistently elevated.