Datta Dibyadeep, Enwright John F, Arion Dominique, Paspalas Constantinos D, Morozov Yury M, Lewis David A, Arnsten Amy F T
Department of Neuroscience, Yale School of Medicine, Yale University, New Haven, CT, United States.
Department of Psychiatry, Translational Neuroscience Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.
Front Neuroanat. 2020 Nov 20;14:578483. doi: 10.3389/fnana.2020.578483. eCollection 2020.
cAMP signaling has powerful, negative effects on cognitive functions of the primate dorsolateral prefrontal cortex (dlPFC), opening potassium channels to reduce firing and impair working memory, and increasing tau phosphorylation in aging neurons. This contrasts with cAMP actions in classic circuits, where it enhances plasticity and transmitter release. PDE4 isozymes regulate cAMP actions, and thus have been a focus of research and drug discovery. Previous work has focused on the localization of PDE4A and PDE4B in dlPFC, but PDE4D is also of great interest, as it is the predominant PDE4 isoform in primate association cortex, and PDE4D expression decreases with aging in human dlPFC. Here we used laser-capture microdissection transcriptomics and found that PDE4D message is enriched in pyramidal cells compared to GABAergic PV-interneurons in layer III of the human dlPFC. A parallel study in rhesus macaques using high-spatial resolution immunoelectron microscopy revealed the ultrastructural locations of PDE4D in primate dlPFC with clarity not possible in human post-mortem tissue. PDE4D was especially prominent in dendrites associated with microtubules, mitochondria, and likely smooth endoplasmic reticulum (SER). There was substantial postsynaptic labeling in dendritic spines, associated with the SER spine-apparatus near glutamatergic-like axospinous synapses, but sparse labeling in axon terminals. We also observed dense PDE4D labeling perisynaptically in astroglial leaflets ensheathing glutamatergic connections. These data suggest that PDE4D is strategically positioned to regulate cAMP signaling in dlPFC glutamatergic synapses and circuits, especially in postsynaptic compartments where it is localized to influence cAMP actions on intracellular trafficking, mitochondrial physiology, and internal calcium release.
环磷酸腺苷（cAMP）信号传导对灵长类动物背外侧前额叶皮层（dlPFC）的认知功能具有强大的负面影响，它通过打开钾通道来减少放电并损害工作记忆，还会增加衰老神经元中的tau蛋白磷酸化。这与经典神经回路中cAMP的作用形成对比，在经典回路中它会增强可塑性和神经递质释放。磷酸二酯酶4（PDE4）同工酶调节cAMP的作用，因此一直是研究和药物发现的重点。先前的工作主要集中在PDE4A和PDE4B在dlPFC中的定位，但PDE4D也备受关注，因为它是灵长类动物联合皮层中主要的PDE4同工型，并且在人类dlPFC中其表达会随着年龄增长而降低。在这里，我们使用激光捕获显微切割转录组学发现，与人类dlPFC第III层中的γ-氨基丁酸能（GABAergic）小白蛋白（PV）中间神经元相比，PDE4D信息在锥体细胞中更为丰富。一项在恒河猴中使用高空间分辨率免疫电子显微镜的平行研究清晰地揭示了PDE4D在灵长类动物dlPFC中的超微结构位置，这在人类死后组织中是无法实现的。PDE4D在与微管、线粒体以及可能的滑面内质网（SER）相关的树突中尤为突出。在树突棘中有大量的突触后标记，与类谷氨酸能轴棘突触附近的SER棘装置相关，但在轴突终末标记稀疏。我们还观察到在包裹谷氨酸能连接的星形胶质细胞小叶的突触周围有密集的PDE4D标记。这些数据表明，PDE4D处于战略位置，可调节dlPFC谷氨酸能突触和神经回路中的cAMP信号传导，尤其是在突触后区室中，它在那里定位以影响cAMP对细胞内运输、线粒体生理学和细胞内钙释放的作用。
