Fn14 is an activity-dependent, Bmal1-regulated cytokine receptor that induces rod-like microglia and restricts neuronal activity in vivo

🥈 Top 2% JournalJan 30, 2026Cell reports

The Fn14 receptor, controlled by brain activity and Bmal1, triggers rod-shaped immune cells and limits nerve cell activity in living brains

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Fn14 expression in pyramidal neurons is induced by activity and environmental enrichment in the hippocampal CA1 region.

Fn14 dampens neuronal activity during the daily light-dark transition.
Regulation of Fn14 expression in CA1 neurons is linked to the circadian transcription factor Bmal1.
Mice lacking Fn14 display disrupted sleep-wake patterns.
Absence of Fn14 leads to microglia contacting fewer excitatory synapses.
Overexpression of Fn14 results in the formation of rod-like microglia and their recruitment to excitatory synapses.
Mice without Fn14 show increased vulnerability to chemically induced seizures.

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Cytokines and their receptors play important roles in brain development and aging-related disease, but their functions within the healthy adult brain remain poorly understood. Here, we show that pyramidal neurons in hippocampal CA1 induce Fn14 expression in response to activity and environmental enrichment. Once expressed, Fn14 dampens the activity of these neurons most prominently at the daily transition between light and dark. Fn14 expression in CA1 neurons is regulated by the circadian transcription factor Bmal1, and mice lacking Fn14 exhibit disrupted sleep-wake patterns in vivo. At the cellular level, microglia contact fewer excitatory synapses in the absence of Fn14, while neuronal overexpression of Fn14 induces rod-like microglia and recruits them to excitatory synapses. Beyond a homeostatic context, mice lacking Fn14 exhibit heightened susceptibility to chemically induced seizures. These findings reveal that pro-inflammatory cytokine receptors such as Fn14 can play major roles in healthy neurological function in the adult brain.

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