LGI1 governs neuritin-mediated resilience to chronic stress

Depression is accompanied by neuronal atrophy and decreased neuroplasticity. Leucine-rich glioma-inactivated protein 1 (LGI1), a metastasis suppressor, plays an important role in the development of CNS synapses. We found that LGI1 expression was reduced in the hippocampi of mice that underwent chronic unpredictable stress (CUS), and could be rescued by the antidepressant, fluoxetine. Recombinant soluble neuritin, an endogenous protein previously implicated in antidepressant-like behaviors, elevated hippocampal LGI1 expression in a manner dependent on histone deacetylase 5 (HDAC5) phosphorylation. Accordingly, Nrn1(flox/flox);Pomc-cre (Nrn1 cOE) mice, which conditionally overexpress neuritin, displayed increases in hippocampal LGI1 level under CUS and exhibited resilience to CUS that were blocked by hippocampal depletion of LGI1. Interestingly, neuritin-mediated LGI1 expression was inhibited by HNMPA-(AM)(3), an insulin receptor inhibitor, as was neuritin-mediated HDAC5 phosphorylation. We thus establish hippocampal LGI1 as an effector of neurite outgrowth and stress resilience, and suggest that HDAC5-LGI1 plays a critical role in ameliorating pathological depression.