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Author Spotlight: Induced Microglia-Like Cell Technology to Shed Light on the Role of Microglial Dysfunction in Neuropsychiatric Disorders
Published on: September 6, 2024
IL-15 receptor alpha deficiency triggers depressive-like behaviors via enhanced microglial synapse pruning
Yue Tang1,2, Yu Huang1,2, Jing Pan1,2
1Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Abstract:
Major Depressive Disorder (MDD) is a serious mental illness, and neuroinflammation is increasingly recognized as a contributor to its pathogenesis; however, the underlying cellular and molecular mechanisms remain largely unknown. In this study, we performed single-nucleus RNA sequencing to profile prefrontal cortex transcriptomics in interleukin-15 receptor subunit alpha knockout (Il15ra-/-) mice displaying depressive-like behaviors. Il15ra-/- mice exhibited cell-type-specific transcriptomic alterations, particularly affecting synapse assembly. Co-expression network analysis identified two gene clusters predominantly linked to synaptic pathways in microglia, excitatory neurons, and interneurons, suggesting dysregulated neuron-microglial interactions in depression. Morphological analysis revealed microglial activation and synapse remodeling driven by enhanced neuron-microglia communication via the CX3CL1/CX3CR1 signaling pathway. Pharmacological inhibition of CX3CL1/CX3CR1 signaling using a CX3CR1 antagonist reversed depressive-like behaviors and microglia-mediated excessive synapse pruning caused by IL-15RA deficiency. Collectively, these findings demonstrate that IL-15RA deficiency contributes to depression onset by modulating microglia-mediated synaptic remodeling, highlighting a targetable neuroimmune pathway for therapeutic interventions in MDD.
Insights
Interleukin-15 receptor alpha (IL-15RA) deficiency in mice triggers neuroinflammation and synaptic changes, contributing to depression. Targeting the CX3CL1/CX3CR1 pathway reversed these effects, offering a potential therapeutic strategy for Major Depressive Disorder (MDD).
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.
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