National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital/Institute of Mental Health, 100191 Beijing, China; Key Laboratory of Mental Health, Ministry of Health, Peking University, 100191 Beijing, China.
Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, 310058 Hangzhou, China.
Cell Rep. 2017 Oct 24;21(4):891-900. doi: 10.1016/j.celrep.2017.10.006.
Calbindin modulates intracellular Ca dynamics and synaptic plasticity. Reduction of hippocampal calbindin levels has been implicated in early-life stress-related cognitive disorders, but it remains unclear how calbindin in distinct populations of hippocampal neurons contributes to stress-induced memory loss. Here we report that early-life stress suppressed calbindin levels in CA1 and dentate gyrus (DG) neurons, and calbindin knockdown in adult CA1 or DG excitatory neurons mimicked early-life stress-induced memory loss. In contrast, calbindin knockdown in CA1 interneurons preserved long-term memory even after an acute stress challenge. These results indicate that the dysregulation of calbindin in hippocampal excitatory, but not inhibitory, neurons conveys susceptibility to stress-induced memory deficits. Moreover, calbindin levels were downregulated by early-life stress through the corticotropin-releasing hormone receptor 1-nectin3 pathway, which in turn reduced inositol monophosphatase levels. Our findings highlight calbindin as a molecular target of early-life stress and an essential substrate for memory.
钙结合蛋白调节细胞内钙动态和突触可塑性。海马钙结合蛋白水平的降低与生命早期应激相关的认知障碍有关，但尚不清楚海马不同神经元群体中的钙结合蛋白如何导致应激引起的记忆丧失。在这里，我们报告说，生命早期的应激会抑制 CA1 和齿状回（DG）神经元中的钙结合蛋白水平，而成年 CA1 或 DG 兴奋性神经元中的钙结合蛋白敲低会模拟生命早期应激引起的记忆丧失。相比之下，CA1 中间神经元中的钙结合蛋白敲低即使在急性应激挑战后也能保留长期记忆。这些结果表明，海马兴奋性神经元中钙结合蛋白的失调会导致对应激引起的记忆缺陷的易感性，而不是抑制性神经元。此外，生命早期的应激通过促肾上腺皮质激素释放激素受体 1-神经细胞黏附分子 3 途径下调钙结合蛋白水平，进而降低肌醇 1-磷酸酶水平。我们的研究结果强调了钙结合蛋白作为生命早期应激的分子靶点和记忆的重要基质。
