Gallo Maria Teresa, Virenque Anaïs, Golinelli Alessia, Fumagalli Fabio, Castrén Eero, Brivio Paola, Calabrese Francesca
Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy.
Neuroscience Center-HILIFE, University of Helsinki, Helsinki, Finland.
Mol Psychiatry. 2025 Sep 9. doi: 10.1038/s41380-025-03223-6.
Early-life experiences shape neural networks, with heightened plasticity during the so-called "sensitive periods" (SP). SP are regulated by the maturation of GABAergic parvalbumin-positive (PV+) interneurons, which become enwrapped by perineuronal nets (PNNs) over time, modulating SP closure. Additionally, the opening and closing of SP are orchestrated by two distinct gene clusters known as "trigger" and "brake". Interestingly alterations in SP markers have been identified in neuropsychiatric disorders, suggesting they may play a role in the emergence of these pathological conditions. Here, we investigate, in rats, whether the behavioral phenotypes observed in adults exposed to fluoxetine (FLX) during gestation or breastfeeding (until postnatal day 21) are due to alterations in SP dynamics. In line with the pathological-like adult phenotypes observed, the molecular results reveal a clear sex difference with significant changes in the density of PV+, in the proportion of PV+ cells surrounded by PNNs, as well as in the expression of trigger and brake genes across the lifespan, in the prefrontal cortex and dorsal hippocampus. In particular, we observed the strongest effect in the dentate gyrus (DG) of the dorsal hippocampus, with an anticipation in prenatal-FLX males and a delay in postnatal-FLX females of SP opening. We suggest that the molecular targets herein described may represent useful biomarkers to identify people with potentially increased vulnerability and, accordingly, we can hypothesize that strategies (pharmacological or not) aimed at correcting these abnormalities may be useful in preventing the pathological manifestation.
早期生活经历塑造神经网络，在所谓的“敏感期”（SP）期间可塑性增强。SP由γ-氨基丁酸能小白蛋白阳性（PV+）中间神经元的成熟所调节，随着时间的推移，这些神经元会被神经周网（PNN）包裹，从而调节SP的关闭。此外，SP的开启和关闭由两个不同的基因簇“触发”和“刹车”协调。有趣的是，在神经精神疾病中已发现SP标记物的改变，这表明它们可能在这些病理状况的出现中起作用。在此，我们在大鼠中研究，孕期或哺乳期（直至出生后第21天）接触氟西汀（FLX）的成年大鼠所观察到的行为表型是否归因于SP动态变化。与所观察到的类似病理的成年表型一致，分子结果显示出明显的性别差异，在前额叶皮质和背侧海马体中，PV+密度、被PNN包围的PV+细胞比例以及整个生命周期中触发和刹车基因的表达均有显著变化。特别是，我们在背侧海马体的齿状回（DG）中观察到最强的效应，产前接触FLX的雄性大鼠SP开启提前，产后接触FLX的雌性大鼠SP开启延迟。我们认为，本文所述的分子靶点可能代表有用的生物标志物，用于识别潜在易感性增加的人群，因此，我们可以推测，旨在纠正这些异常的策略（无论是否为药理学策略）可能有助于预防病理表现。
