Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice

Area of Science:

• Neuroscience
• Immunology
• Developmental Biology

Background:

• Microglia are key players in brain development, clearing synaptic material during synapse remodeling.
• The environmental cues and molecular mechanisms guiding microglial synapse remodeling remain incompletely understood.

Purpose of the Study:

• To investigate the regulatory mechanisms of microglia function downstream of interleukin-33 (IL-33).
• To explore the role of IL-33 in modulating microglial epigenetic landscapes and gene expression.
• To determine the impact of IL-33 signaling on synaptic development and neuronal excitability.

Main Methods:

• Analysis of microglial enhancer landscapes and transcription factor binding following IL-33 exposure.
• RNA sequencing to identify IL-33-induced gene expression programs.
• Generation of CNS-specific IL-33 knockout mice and MARCO-deficient mice.
• Electrophysiological recordings and seizure susceptibility tests in mouse models.

Main Results:

• IL-33 stimulation altered microglial epigenetics, increasing AP-1/FOS binding and upregulating pattern recognition receptors, including MARCO.
• CNS-specific IL-33 deletion resulted in synaptic imbalance, absence-like seizures, and heightened seizure susceptibility.
• MARCO deficiency led to excessive thalamic excitatory synapses and increased seizure susceptibility, indicating its role in synapse engulfment.

Conclusions:

• IL-33 orchestrates epigenetic and functional changes in microglia, impacting postnatal synaptic refinement.
• Pattern recognition receptors, such as MARCO, are identified as critical regulators of microglial synapse pruning.
• Dysregulation of the IL-33/MARCO pathway contributes to aberrant synaptic development and epilepsy.