Inhibition of stress resilience and adult hippocampal neurogenesis by platelet-derived LPA16:0 in anxiety

Anxiety is an aggravating comorbidity of many psychiatric disorders that is often underdiagnosed and undertreated, and little is known on the mechanisms underlying its regulation. Here, we find that serum LPA16:0 abundance increases with trait anxiety in both humans and mice; while high LPA16:0 levels are sufficient to reduce the in vitro proliferation of adult hippocampal neural stem/progenitor cells. In humans, the main LPA receptor LPA₁, bears single nucleotide polymorphism variants associated with anxiety. In mice, LPA16:0 decreases hippocampal neurogenesis and stress resilience, whereas LPA₁ antagonism or the reduction of platelets, the main source of circulating LPA16:0, increases adult neurogenesis and resilience to acute stress. Conditional knockdown of LPA₁ receptor in neural stem cells is sufficient to enhance cell proliferation in the dentate gyrus. Finally, the inhibition of adult neurogenesis abolishes the beneficial effect of LPA₁ antagonism on resilience against both acute and chronic stress. Together, these findings identify circulating LPA16:0 as a biomarker of trait anxiety and LPA16:0-LPA₁ signaling as a regulation mechanism of mood-related behavior through the decrease of adult neurogenesis.