C1ql2 gates stress vulnerability by regulating microglia-mediated synaptic pruning in the BLA-vHPC circuit.

Synaptic remodeling in emotional circuits contributes to the development of stress-related emotional disorders. However, such remodeling generally exhibits considerable heterogeneity across specific neuronal populations and the underlying molecular mechanisms remain poorly understood. Here, we identified C1ql2 as a key molecular regulator that governs projection-specific synaptic vulnerability within basolateral amygdala (BLA). Transcriptional profiling revealed that C1ql2 expression is enriched in BLA neurons projecting to ventral hippocampus (BLA→vHPC PNs), but not in those projecting to nucleus accumbens (NAc), and is significantly down-regulated following chronic social defeat stress (CSDS). Gain- and loss-of-function manipulations demonstrated that C1ql2 regulates stress-induced neuronal remodeling in BLA→vHPC PNs, including dendritic hypertrophy, synaptic outgrowth, and enhanced glutamatergic transmission, thereby shaping susceptibility to anxiety-like behavior. We further found that CSDS-induced C1ql2 loss impairs microglial engulfment of BLA→vHPC PNs synapses, leading to aberrant synaptic accumulation. Our findings establish C1ql2-mediated neuron-microglia cross talk that critically regulates circuit-specific synaptic pathophysiology in stress-related disorders.