IL-15 Receptor Deficiency Drives Depressive Behaviors via Microglial Synapse Pruning in Mice

Major depressive disorder is increasingly recognized as a systemic illness driven by complex interactions between the immune system and central nervous system architecture [1, 2, 3]. While traditional theories focused on neurotransmitter depletion, contemporary evidence highlights the role of neuroinflammation and the activation of resident immune cells in the brain [4, 5]. These microglial cells, which normally maintain homeostasis and prune redundant connections, can become dysregulated under chronic stress, leading to aberrant synaptic remodeling [6, 7]. Recent transcriptomic analysis using single-nucleus RNA sequencing (a technique that identifies gene expression in individual cell nuclei) reveals that deficiency in the interleukin-15 receptor alpha (IL-15RA) subunit triggers excessive synapse pruning in the prefrontal cortex [8]. This pathological remodeling is mediated by the CX3CL1/CX3CR1 signaling pathway, and pharmacological inhibition of this axis has been shown to reverse depressive-like behaviors in animal models [8, 9]. Such structural changes in neural circuits are thought to underpin the persistent mood and cognitive deficits seen in clinical practice [10, 3].