Buonaguro Elisabetta F, Morley-Fletcher Sara, Avagliano Camilla, Vellucci Licia, Iasevoli Felice, Bouwalerh Hammou, Van Camp Gilles, Nicoletti Ferdinando, Maccari Stefania, de Bartolomeis Andrea
Laboratory of Molecular and Translational Psychiatry, Unit of Treatment Resistant Psychosis, Section of Psychiatry and Psychology, Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy.
Universiy of Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France; International Associated Laboratory (LIA), "Prenatal Stress and Neurodegenerative Diseases", University of Lille - CNRS, UMR 8576, and Sapienza University of Rome, IRCCS Neuromed, Italy.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jan 10;96:109725. doi: 10.1016/j.pnpbp.2019.109725. Epub 2019 Aug 9.
Type-5 metabotropic glutamate receptors (mGlu5) have been implicated in the mechanism of resilience to stress. They form part of the postsynaptic density (PSD), a thickening of the glutamatergic synapse that acts as a multimodal hub for multiple cellular signaling. Perinatal stress in rats triggers alterations that make adult offspring less resilient to stress. In the present study, we examined the expression of gene encoding the mGlu5 (Grm5), as well as those encoding the short and long isoforms of Homer proteins in different brain regions of the offspring of dams exposed to repeated episodes of restraint stress during pregnancy ("perinatally stressed" or PRS offspring). To this end, we investigated unconditioned behavioral response using the light/dark box test, as well as the expression of PSD genes (Homer1a, Homer1b, and Grm5), in the medial prefrontal cortex, cortex, caudate-putamen, amygdala, and dorsal hippocampus. PRS rats spent significantly less time in the light area than the control group. In the amygdala, Homer1a mRNA levels were significantly increased in PRS rats, whereas Homer1b and Grm5 mRNA levels were reduced. In contrast, the transcript encoding for Homer1a was significantly reduced in the medial prefrontal cortex, caudate-putamen, and dorsal hippocampus of PRS rats. We also evaluated the relative ratio between Homer1a and Homer1b/Grm5 expression, finding a significant shift toward the expression of Homer1a in the amygdala and toward Homer1b/Grm5 in the other brain regions. These topographic patterns of Homer1a, Homer1b, and mGlu5 gene expression were significantly correlated with risk-taking behavior measured in the light/dark box test. Remarkably, in the amygdala and in other brain regions, Homer1b and Grm5 expression showed positive correlation with time spent in the light box, whereas Homer1a in the amygdala showed a negative correlation with risk-taking behavior, in contrast with all other brain regions analyzed, wherein these correlations were positive. These results suggest that perinatal stress programs the developmental expression of PSD molecules involved in mGlu5 signaling in discrete brain regions, with a predominant role for the amygdala.
5型代谢型谷氨酸受体（mGlu5）与应激恢复力机制有关。它们是突触后致密区（PSD）的一部分，PSD是谷氨酸能突触的增厚部分，作为多种细胞信号传导的多模式枢纽。大鼠围产期应激会引发一些改变，使成年后代对应激的恢复力降低。在本研究中，我们检测了在孕期遭受反复束缚应激的母鼠后代（“围产期应激”或PRS后代）不同脑区中编码mGlu5的基因（Grm5）以及编码荷马蛋白短异构体和长异构体的基因的表达。为此，我们使用明暗箱试验研究了非条件行为反应，以及内侧前额叶皮质、皮质、尾状核 - 壳核、杏仁核和背侧海马中PSD基因（Homer1a、Homer1b和Grm5）的表达。PRS大鼠在亮区停留的时间明显少于对照组。在杏仁核中，PRS大鼠的Homer1a mRNA水平显著升高，而Homer1b和Grm5 mRNA水平降低。相反，在PRS大鼠的内侧前额叶皮质、尾状核 - 壳核和背侧海马中，编码Homer1a的转录本显著减少。我们还评估了Homer1a与Homer1b/Grm5表达之间的相对比率，发现在杏仁核中表达明显向Homer1a偏移，而在其他脑区则向Homer1b/Grm5偏移。Homer1a、Homer1b和mGlu5基因表达的这些地形模式与明暗箱试验中测量的冒险行为显著相关。值得注意的是，在杏仁核和其他脑区，Homer1b和Grm5表达与在亮箱中停留的时间呈正相关，而杏仁核中的Homer1a与冒险行为呈负相关，这与所有其他分析的脑区相反，在这些脑区中这些相关性是正的。这些结果表明，围产期应激对离散脑区中参与mGlu5信号传导的PSD分子的发育表达进行了编程，杏仁核起主要作用。
