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

Neuron-microglia interactions dictate the development of neuronal circuits in the brain. However, the factors that support and broadly regulate these processes across developmental stages are largely unknown. Here, we find that IL34, a neuron-derived cytokine, is upregulated in development and plays a critical role in supporting and maintaining neuroprotective, mature microglia in the anterior cingulate cortex (ACC) of mice. We show that IL34 mRNA and protein is upregulated in neurons in the second week of postnatal life and that this increase coincides with increases in microglia number and expression of mature, homeostatic markers, e.g., TMEM119. We also found that IL34 mRNA is higher in excitatory (compared to inhibitory) neurons. Global genetic KO of IL34 reduced microglia numbers and prevented the functional maturation of microglia, and excitatory-neuron specific KO of IL34 similarly impacted microglia and increased aberrant microglial phagocytosis of excitatory thalamocortical synapses in the ACC. Acute, low dose blocking of IL34 at postnatal day (P)15 in mice decreased microglial TMEM119 protein and also increased microglial phagocytosis of excitatory thalamocortical synapses during an inappropriate time in development. In contrast, viral overexpression of IL34 early in life (P1-P8) caused early maturation of microglia and prevented microglial phagocytosis of thalamocortical synapses during the appropriate neurodevelopmental refinement window. Taken together, these findings establish IL34 as a key regulator of neuron microglia crosstalk in postnatal brain development, controlling both microglial maturation and synapse engulfment.