Neuron Derived Cytokine Interleukin-34 Controls Developmental Microglia Function.
Benjamin A DevlinDang M NguyenGabriel GrullonMadeline J ClarkAlexis M CeasrineMartha DejaAshka ShahShomik AtiAmelie FinnDiogo RibeiroAnne SchaeferStaci D BilboPublished in: bioRxiv : the preprint server for biology (2024)
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 more active neurons, and higher in excitatory (compared to inhibitory) neurons. Genetic KO of IL34 prevents the functional maturation of microglia and results in an anxiolytic phenotype in these mice by adulthood. Acute, low dose blocking of IL34 at postnatal day (P)15 in mice decreased microglial TMEM119 expression and increased aberrant microglial phagocytosis of thalamocortical synapses within the ACC. 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.
Keyphrases
- inflammatory response
- neuropathic pain
- spinal cord
- low dose
- lipopolysaccharide induced
- lps induced
- preterm infants
- poor prognosis
- binding protein
- spinal cord injury
- magnetic resonance
- randomized controlled trial
- intensive care unit
- high dose
- cell proliferation
- white matter
- cerebral ischemia
- depressive symptoms
- dna methylation
- genome wide
- functional connectivity
- magnetic resonance imaging
- hepatitis b virus
- small molecule
- skeletal muscle
- high fat diet induced
- subarachnoid hemorrhage
- amino acid
- respiratory failure
- congenital heart disease
- drug induced