The genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex.
The genie in the bottle-magnified calcium signaling in dorsolateral prefrontal cortex.
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DOI：
10.1038/s41380-020-00973-3
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发表时间：
2021-08
影响因子：
11
通讯作者：
Wang M
中科院分区：
文献类型：
--
作者：
Arnsten AFT;Datta D;Wang M
在精神分裂症和阿尔茨海默病等认知障碍中，联合皮质的神经元尤其脆弱，而初级视觉皮质的神经元则相对有韧性。这篇综述提出，当由于遗传和/或环境损伤导致调节丧失时，高级认知操作所需的特殊分子机制会使神经元易出现功能障碍、萎缩和神经退行性变。越来越多的数据表明，高级皮质回路依赖于突触后密度附近放大水平的钙（来自N - 甲基 - D - 天冬氨酸受体、钙通道和/或内质网的内部释放）来促进在没有“自下而上”的感觉刺激时维持、操作和存储信息所需的持续放电。例如，灵长类动物背外侧前额叶皮质（dlPFC）的树突棘表达用于前馈、环磷腺苷 - 蛋白激酶A - 钙信号传导的分子机制。蛋白激酶A可以驱动内部钙释放，并促进钙通过N - 甲基 - D - 天冬氨酸受体和钙通道流动，反过来，钙激活腺苷酸环化酶以产生更多的环磷腺苷 - 蛋白激酶A信号传导。过高水平的环磷腺苷 - 钙信号传导会产生许多有害影响：例如，打开附近的钾离子通道以削弱突触效能并减少神经元放电，并且在较长时间内，促使线粒体钙超载以引发炎症和树突萎缩。因此，钙 - 环磷腺苷信号传导必须受到严格调节，例如通过分解环磷腺苷或抑制其产生的物质（磷酸二酯酶4、代谢型谷氨酸受体3），以及通过在细胞质中结合钙的蛋白质（钙结合蛋白）。生命早期的许多遗传或炎症损伤会削弱钙 - 环磷腺苷信号传导的调节，并与精神分裂症风险增加相关（例如，代谢型谷氨酸受体3基因）。在较长寿命期间，与年龄相关的调节蛋白缺失会导致钙 - 环磷腺苷信号传导升高，这还会促使tau蛋白磷酸化、淀粉样病变和神经退行性变，特别是当细胞质中保护性的钙结合蛋白缺失时。因此，我们卓越的认知能力所依赖的“精灵”可能会在我们失去必要的调节时使我们易患认知障碍。
Neurons in the association cortices are particularly vulnerable in cognitive disorders such as schizophrenia and Alzheimer’s Disease, while those in primary visual cortex remain relatively resilient. This review proposes that the special molecular mechanisms needed for higher cognitive operations confer vulnerability to dysfunction, atrophy and neurodegeneration when regulation is lost due to genetic and/or environmental insults. Accumulating data suggest that higher cortical circuits rely on magnified levels of calcium (from NMDAR, calcium channels, and/or internal release from the smooth endoplasmic reticulum) near the postsynaptic density to promote the persistent firing needed to maintain, manipulate and store information without “bottom-up” sensory stimulation. For example, dendritic spines in the primate dorsolateral prefrontal cortex (dlPFC) express the molecular machinery for feedforward, cAMP-PKA-calcium signaling. PKA can drive internal calcium release and promote calcium flow through NMDAR and calcium channels, while in turn, calcium activates adenylyl cyclases to produce more cAMP-PKA signaling. Excessive levels of cAMP-calcium signaling can have a number of detrimental effects: e.g. opening nearby K+ channels to weaken synaptic efficacy and reduce neuronal firing, and over a longer timeframe, driving calcium overload of mitochondria to induce inflammation and dendritic atrophy. Thus, calcium-cAMP signaling must be tightly regulated, e.g. by agents that catabolize cAMP or inhibit its production (PDE4, mGluR3), and by proteins that bind calcium in the cytosol (calbindin). Many genetic or inflammatory insults early in life weaken the regulation of calcium-cAMP signaling and are associated with increased risk of schizophrenia (e.g. GRM3). Age-related loss of regulatory proteins which result in elevated calcium-cAMP signaling over a long lifespan can additionally drive tau phosphorylation, amyloid pathology and neurodegeneration, especially when protective calcium binding proteins are lost from the cytosol. Thus, the “genie” we need for our remarkable cognitive abilities may make us vulnerable to cognitive disorders when we lose essential regulation.
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影响因子：
34.7
作者：
Arnsten, Amy F. T.
通讯作者：
Arnsten, Amy F. T.
影响因子：
10.6
作者：
Ansell, Emily B.;Rando, Kenneth;Tuit, Keri;Guarnaccia, Joseph;Sinha, Rajita
通讯作者：
Sinha, Rajita
DOI：
10.1038/ejhg.2015.218
发表时间：
2016-06
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
Ambalavanan A;Girard SL;Ahn K;Zhou S;Dionne-Laporte A;Spiegelman D;Bourassa CV;Gauthier J;Hamdan FF;Xiong L;Dion PA;Joober R;Rapoport J;Rouleau GA
通讯作者：
Rouleau GA
影响因子：
3.7
作者：
Arnold, Steven E.;Hyman, Bradley T.;Van Hoesen, Gary W.
通讯作者：
Van Hoesen, Gary W.
影响因子：
16.2
作者：
Arnsten AF;Wang MJ;Paspalas CD
通讯作者：
Paspalas CD