Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder

Anxiety disorders are accompanied by changes in brain plasticity, stress vulnerability and heightened risk of depression. Here, we found that serum LPA16:0 abundance increased with trait anxiety in both human and mice and was sufficient to reduce the proliferation of adult hippocampal neural stem/progenitor cells. In humans, the main LPA receptor, LPA ₁ , bears single nucleotide polymorphism variants associated with anxiety. In mice, LPA16:0 decreased hippocampal neurogenesis and stress resilience, whereas LPA ₁ antagonism or the reduction of platelets, the main source of circulating LPA16:0, increased adult neurogenesis and resilience to acute stress. Finally, the inhibition of adult neurogenesis abolished the beneficial effect of LPA ₁ antagonism on resilience against both acute and chronic stress.

Together, these findings identify LPA16:0-LPA ₁ signaling as a regulation mechanism of adult neurogenesis and a potential therapeutic target for mood disorders.