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.

抑郁症伴随着神经元萎缩和神经可塑性降低。富含亮氨酸的胶质瘤灭活蛋白 1 (LGI1) 是一种转移抑制因子，在 CNS 突触的发育中起着重要作用。我们发现 LGI1 在经受慢性不可预测压力 (CUS) 的小鼠海马中的表达降低，并且可以被抗抑郁药氟西汀挽救。重组可溶性神经蛋白，一种先前参与抗抑郁样行为的内源性蛋白质，以依赖于组蛋白去乙酰化酶 5 (HDAC5) 磷酸化的方式提高海马 LGI1 表达。因此，Nrn1 ^flox/flox ; Pomc-cre ( Nrn1cOE) 小鼠有条件地过度表达神经蛋白，在 CUS 下表现出海马 LGI1 水平的增加，并表现出对 CUS 的恢复力，这些恢复力被海马区 LGI1 耗竭所阻断。有趣的是，神经蛋白酶介导的 LGI1 表达被胰岛素受体抑制剂HNMPA-(AM) ₃抑制，神经蛋白酶介导的 HDAC5 磷酸化也是如此。因此，我们将海马 LGI1 确立为神经突生长和压力恢复的效应物，并表明 HDAC5-LGI1 在改善病理性抑郁症中起着关键作用。