Microglia specific Csf1r haploinsufficiency induces depressive-like behaviors by promoting NLRP6/caspase-1 signaling in mice.

Depression is an early clinical manifestation of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), although the underlying molecular mechanisms remain poorly elucidated. The objective of this study was to investigate the mechanisms underpinning depressive behavior in the context of ALSP, utilizing microglial-specific Csf1r haploinsufficient mice. Our findings indicate that these mice exhibited depressive-like behaviors, as well as microglial hyper-ramification and aberrant synaptic pruning capacity. Blockade of CSF1R signaling with PLX3397 resulted in significant amelioration of depressive symptoms and restoration of normal microglial morphology and function. RNA sequencing analysis of microglia isolated from the medial prefrontal cortex (mPFC) of the brain indicated that NLRPs signaling pathways may play a significant role in the observed alterations in microglial Csf1r haploinsufficient mice. Notably, NLRP6, rather than NLRP3, was found to be upregulated, and the expression of caspase-1 exhibited colocalization with the microglial marker Iba1. Pharmacological inhibition of caspase-1 using VX-765 improved depressive-like behaviors, as well as microglial function. Taken together, our findings delineate a causal relationship between microglial Csf1r haploinsufficiency-induced activation of the NLRP6/caspase-1 signaling pathway and the manifestation of depressive-like behaviors in ALSP mice.