Excitatory Neuron-Derived Interleukin-34 Controls Cortical Developmental Microglia Function

Microglia play critical roles in brain development, but the specific molecular cues that guide their functional transition from immature, developmental states to mature, homeostatic ones are largely unknown. This study investigates the role of Interleukin-34 (IL34), a neuron-derived cytokine, as a potential regulator of microglial maturation and synaptic remodeling during the second postnatal week in the mouse anterior cingulate cortex (ACC).

Researchers employed a multi-faceted approach, including gene expression profiling over developmental time, genetic knockouts (both global and excitatory neuron-specific), viral overexpression, and acute pharmacological blockade using neutralizing antibodies. They specifically used 3D imaging and reconstructions in the ACC to measure microglial lysosomal content and the engulfment of thalamocortical synaptic material. Furthermore, they conducted RNA sequencing of isolated microglia to assess changes in transcriptional maturation indices.

IL34 expression increases significantly in the mouse forebrain during the second postnatal week, coinciding with microglial maturation. Excitatory neurons, particularly glutamatergic subtypes, were identified as the primary source of this IL34. Genetic ablation or acute antibody-mediated blockade of IL34 resulted in a persistent 'immature' microglial state characterized by lower levels of TMEM119 and P2YR12, increased lysosomal activity, and excessive, aberrant engulfment of excitatory thalamocortical synapses. Conversely, viral overexpression of IL34 in the prefrontal cortex was sufficient to accelerate microglial maturation and suppress synaptic pruning, suggesting that IL34 acts as a 'don't eat me' signal or a brake on phagocytic activity in the developing cortex.

These results establish IL34 as a key regulator of neuron-microglia crosstalk during a critical developmental window. By showing that IL34 acts as a functional brake on microglial synaptic pruning, the study provides a mechanistic link between neuronal signaling and the refinement of neural circuits. These findings also position IL34 as a potential therapeutic target, given its known involvement in several neurodegenerative conditions and the observed behavioral shifts—such as reduced anxiety—resulting from its developmental disruption.