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. 2025 Aug 12;58(8):1948-1965.e6.
doi: 10.1016/j.immuni.2025.06.002. Epub 2025 Jul 2.

Excitatory-neuron-derived interleukin-34 supports cortical developmental microglia function

Benjamin A Devlin  1 , Dang M Nguyen  1 , Diogo Ribeiro  2 , Gabriel Grullon  1 , Madeline J Clark  3 , Amelie Finn  1 , Alexis M Ceasrine  1 , Seneca Oxendine  1 , Martha Deja  1 , Ashka Shah  1 , Shomik Ati  1 , Anne Schaefer  2 , Staci D Bilbo  4
Affiliations

Excitatory-neuron-derived interleukin-34 supports cortical developmental microglia function

Benjamin A Devlin et al. Immunity. .

Abstract

Neuron-microglia interactions dictate the development of neuronal circuits in the brain. However, the factors that regulate these processes across development are largely unknown. Here, we found that interleukin-34 (IL-34), a neuron-derived cytokine, was upregulated in early development and maintained neuroprotective, mature microglia in the anterior cingulate cortex (ACC) of mice. IL-34 expression increases in the second week of post-natal life and was primarily produced by excitatory neurons. Excitatory-neuron-specific deletion of IL-34 reduced microglia numbers and microglial TMEM119 expression and increased aberrant microglial phagocytosis of excitatory thalamocortical synapses in the ACC. Acute, low-dose blocking of IL-34 at post-natal day 15 similarly decreased microglial TMEM119 and aberrantly increased microglial phagocytosis of synapses. Viral overexpression of IL-34 induced TMEM119 expression and prevented appropriate microglial phagocytosis of synapses. These findings establish IL-34 as a key regulator of neuron-microglia crosstalk in post-natal brain development, controlling both microglial maturation and synapse engulfment.

Keywords: CSF-1R; Il-34; TMEM119; behavior; development; microglia; neuroimmune; phagocytosis; synapse.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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