IL-15 receptor alpha deficiency triggers depressive-like behaviors via enhanced microglial synapse pruning

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Major Depressive Disorder (MDD) is linked to neuroinflammation, but underlying mechanisms are unclear.
• Interleukin-15 receptor subunit alpha (IL-15RA) role in MDD pathogenesis requires further investigation.

Purpose of the Study:

• To investigate the impact of IL-15RA deficiency on brain transcriptomics and behavior in mice.
• To elucidate the cellular and molecular mechanisms of IL-15RA deficiency in depression-like behaviors.

Main Methods:

• Single-nucleus RNA sequencing of the prefrontal cortex in IL-15RA knockout mice.
• Co-expression network analysis to identify gene clusters and pathways.
• Morphological analysis of microglia and synapses.
• Pharmacological inhibition of the CX3CL1/CX3CR1 signaling pathway.

Main Results:

• IL-15RA deficiency caused cell-type-specific transcriptomic alterations, impacting synapse assembly.
• Dysregulated neuron-microglial interactions were identified, involving the CX3CL1/CX3CR1 pathway.
• Microglial activation and excessive synapse pruning were observed in IL-15RA knockout mice.
• Inhibition of CX3CL1/CX3CR1 signaling reversed depression-like behaviors and synaptic abnormalities.

Conclusions:

• IL-15RA deficiency contributes to MDD onset by altering microglia-mediated synaptic remodeling.
• The CX3CL1/CX3CR1 signaling pathway is a critical mediator of these effects.
• Targeting this neuroimmune pathway presents a potential therapeutic strategy for MDD.