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Unique Molecular Regulation of Higher-Order Prefrontal Cortical Circuits: Insights into the Neurobiology of Schizophrenia.
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2018-03-01 , DOI: 10.1021/acschemneuro.7b00505
Dibyadeep Datta 1 , Amy F T Arnsten 1
Affiliation  

Schizophrenia is associated with core deficits in cognitive abilities and impaired functioning of the newly evolved prefrontal association cortex (PFC). In particular, neuropathological studies of schizophrenia have found selective atrophy of the pyramidal cell microcircuits in deep layer III of the dorsolateral PFC (dlPFC) and compensatory weakening of related GABAergic interneurons. Studies in monkeys have shown that recurrent excitation in these layer III microcircuits generates the precisely patterned, persistent firing needed for working memory and abstract thought. Importantly, excitatory synapses on layer III spines are uniquely regulated at the molecular level in ways that may render them particularly vulnerable to genetic and/or environmental insults. Glutamate actions are remarkably dependent on cholinergic stimulation, and there are inherent mechanisms to rapidly weaken connectivity, e.g. during stress. In particular, feedforward cyclic adenosine monophosphate (cAMP)-calcium signaling rapidly weakens network connectivity and neuronal firing by opening nearby potassium channels. Many mechanisms that regulate this process are altered in schizophrenia and/or associated with genetic insults. Current data suggest that there are "dual hits" to layer III dlPFC circuits: initial insults to connectivity during the perinatal period due to genetic errors and/or inflammatory insults that predispose the cortex to atrophy, followed by a second wave of cortical loss during adolescence, e.g. driven by stress, at the descent into illness. The unique molecular regulation of layer III circuits may provide a nexus where inflammation disinhibits the neuronal response to stress. Understanding these mechanisms may help to illuminate dlPFC susceptibility in schizophrenia and provide insights for novel therapeutic targets.

中文翻译:

高阶前额叶皮层回路的独特分子调控:精神分裂症的神经生物学见解。

精神分裂症与认知能力的核心缺陷和新近发展的前额叶联想皮层(PFC)的功能受损有关。尤其是,精神分裂症的神经病理学研究发现背外侧PFC(dlPFC)的深层III中锥体细胞微回路选择性萎缩,并且相关GABA能中神经元的代偿性减弱。对猴子的研究表明,在这些第III层微电路中的反复激励会产生工作记忆和抽象思维所需的精确图案化的持续放电。重要的是,在第III层棘突上的兴奋性突触在分子水平上受到独特的调节,可能使其特别容易受到遗传和/或环境侵害。谷氨酸的作用明显取决于胆碱能刺激,并且存在一些内在的机制可以快速减弱连接性,例如在压力期间。特别是,前馈环状单磷酸腺苷(cAMP)-钙信号通过打开附近的钾通道而迅速削弱网络连接性和神经元放电。调节该过程的许多机制在精神分裂症中被改变和/或与遗传损伤相关。当前数据表明,III层dlPFC回路受到“双重打击”:由于遗传错误和/或使皮层容易萎缩的炎症性感染,围产期最初对连通性的侮辱,然后在青春期出现第二波皮质损失例如由于压力而导致的疾病。第III层回路的独特分子调节作用可能会在炎症抑制神经元对压力的反应时提供联系。了解这些机制可能有助于阐明精神分裂症中dlPFC的易感性,并为新型治疗靶点提供见解。
更新日期:2018-02-22
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