Dysfunction of Microglial STAT3 Alleviates Depressive Behavior via Neuron-Microglia Interactions

Area of Science:

• Neuroscience
• Immunology
• Psychiatry

Background:

• Neuron-microglia interactions are vital for neuroimmune system homeostasis.
• Dysregulation of the neuroimmune system is implicated in depression pathophysiology.
• The precise role of neuron-microglia communication in major depressive disorders remains unclear.

Purpose of the Study:

• To investigate the contribution of microglia-specific signal transducer and activator of transcription 3 (STAT3) to depression-related behaviors.
• To elucidate the molecular mechanisms underlying microglial regulation of neuronal function in the context of depression.

Main Methods:

• Utilized microglia-specific STAT3 knockout (STAT3^fl/fl;LysM-Cre^+/-) mice.
• Assessed depression-like behaviors using established tests (forced swim, tail suspension, sucrose preference, open-field).
• Measured macrophage colony-stimulating factor (M-CSF) secretion, mediator phosphorylation, and brain-derived neurotrophic factor (BDNF) expression.
• Recorded miniature excitatory postsynaptic current (mEPSC) frequency in the medial prefrontal cortex.

Main Results:

• Microglia-specific STAT3 knockout mice exhibited significant antidepressive-like behaviors.
• Increased M-CSF secretion was observed in neurons of STAT3 knockout mice.
• M-CSF stimulation enhanced phosphorylation of antidepressant-targeting mediators and BDNF expression.
• Enhanced mEPSC frequency in the medial prefrontal cortex was noted in both STAT3 knockout and M-CSF treated groups.

Conclusions:

• Microglial STAT3 plays a critical role in regulating depression-related behaviors.
• The mechanism involves M-CSF-mediated modulation of neuronal synaptic activity.
• Inhibiting microglial STAT3 presents a potential therapeutic strategy for depression.