Unusual Molecular Regulation of Dorsolateral Prefrontal Cortex Layer III Synapses Increases Vulnerability to Genetic and Environmental Insults in Schizophrenia.
Unusual Molecular Regulation of Dorsolateral Prefrontal Cortex Layer III Synapses Increases Vulnerability to Genetic and Environmental Insults in Schizophrenia.
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DOI：
10.1016/j.biopsych.2022.02.003
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发表时间：
2022-09-15
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
精神分裂症与背外侧前额叶皮层（dlPFC）第III层的树突棘和树突数量减少有关，该层包含为工作记忆和抽象思维服务的循环兴奋性微电路。为什么这些突触如此脆弱，而更深层或更表层的突触却几乎不受影响呢？这篇综述描述了在灵长类动物dlPFC中控制第III层神经传递和神经调节的特殊分子特性，以及它们如何使这些电路特别容易受到遗传和环境损伤的影响。这些特性包括依赖N -甲基 - D -天冬氨酸受体（NMDAR）而非α -氨基 - 3 -羟基 - 5 -甲基 - 4 -异恶唑丙酸受体（AMPAR）进行神经传递，在树突棘的谷氨酸能突触附近环磷酸腺苷（cAMP）放大钙信号，以及由环磷酸腺苷 - 蛋白激酶A（cAMP - PKA）信号打开的钾通道动态改变网络强度，并具有在应激期间使dlPFC“离线”的内在机制。多种遗传和/或环境损伤可导致第III层连接性减弱的相同表型，即正常增强连接性的机制受损，而正常减弱连接性的机制增强。诸如犬尿喹啉酸增加和谷氨酸羧肽酶II（GCPII）表达增加等炎症机制对第III层dlPFC的神经传递和调节尤其有害，类似于遗传损伤。遗传和炎症损伤的共同作用可能越过阈值而导致病理变化。
Schizophrenia is associated with reduced numbers of spines and dendrites from layer III of the dorsolateral prefrontal cortex (dlPFC), the layer that houses the recurrent excitatory microcircuits that subserve working memory and abstract thought. Why are these synapses so vulnerable, while those in deeper or more superficial layers are little affected? This review describes the special molecular properties that govern layer III neurotransmission and neuromodulation in the primate dlPFC, and how they may render these circuits particularly vulnerable to genetic and environmental insults. These properties include a reliance on NMDAR rather than AMPAR neurotransmission, cAMP magnification of calcium signaling near the glutamatergic synapse of dendritic spines, and potassium channels opened by cAMP-PKA signaling that dynamically alter network strength, with built-in mechanisms to take dlPFC “off-line” during stress. A variety of genetic and/or environmental insults can lead to the same phenotype of weakened layer III connectivity, where mechanisms that normally strengthen connectivity are impaired, and those that normally weaken connectivity are intensified. Inflammatory mechanisms such as increased kynurenic acid and GCPII expression are especially detrimental to layer III dlPFC neurotransmission and modulation, mimicking genetic insults. The combination of genetic and inflammatory insults may cross the threshold into pathology.
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影响因子：
34.7
作者：
Arnsten, Amy F. T.
通讯作者：
Arnsten, Amy F. T.
DOI：
10.1176/appi.ajp.2009.08091445
发表时间：
2009-07
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Ghose S;Gleason KA;Potts BW;Lewis-Amezcua K;Tamminga CA
通讯作者：
Tamminga CA
影响因子：
10.6
作者：
Datta D;Arion D;Corradi JP;Lewis DA
通讯作者：
Lewis DA
DOI：
10.1002/alz.12325
发表时间：
2021-06
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Datta D;Leslie SN;Wang M;Morozov YM;Yang S;Mentone S;Zeiss C;Duque A;Rakic P;Horvath TL;van Dyck CH;Nairn AC;Arnsten AFT
通讯作者：
Arnsten AFT
影响因子：
10.5
作者：
BALDESSARINI, RJ;HUSTONLYONS, D;COHEN, BM
通讯作者：
COHEN, BM