De Stasi Angela Michela, Zorrilla de San Martin Javier, Soto Nina, Aguirre Andrea, Olusakin Jimmy, Lourenço Joana, Gaspar Patricia, Bacci Alberto
Sorbonne Université, ICM-Paris Brain Institute, CNRS, INSERM, Paris 75013, France.
INSERM UMRS-839 Institut du Fer à Moulin, Paris 75005, France.
J Neurosci. 2025 Feb 5;45(6):e2393232024. doi: 10.1523/JNEUROSCI.2393-23.2024.
The prefrontal cortex (PFC) plays a key role in high-level cognitive functions and emotional behaviors, and PFC alterations correlate with different brain disorders including major depression and anxiety. In mice, the first two postnatal weeks represent a critical period of high sensitivity to environmental changes. In this temporal window, serotonin (5-HT) levels regulate the wiring of PFC cortical neurons. Early-life insults and postnatal exposure to the selective serotonin reuptake inhibitor fluoxetine (FLX) affect PFC development leading to depressive and anxiety-like phenotypes in adult mice. However, the mechanisms responsible for these dysfunctions remain obscure. We found that early postnatal FLX exposure (PNFLX) results in reduced overall firing and high-frequency bursting of putative pyramidal neurons (PNs) of deep layers of the medial PFC of adult mice of both sexes in vivo. Ex vivo, patch-clamp recordings revealed that PNFLX abolished high-frequency firing in a distinct subpopulation of deep-layer mPFC PNs, which transiently express the serotonin transporter SERT during the first 2 postnatal weeks. SERT+ and SERT- PNs exhibit distinct morphofunctional properties. Genetic deletion of 5-HT7Rs and pharmacological 5-HT7R blockade partially rescued both the PNFLX-induced reduction of PN firing in vivo and the altered firing of SERT+ PNs in vitro. This indicates a pivotal role of this 5-HTR subtype in mediating 5-HT-dependent maturation of PFC circuits that are susceptible to early-life insults. Overall, our results suggest potential novel neurobiological mechanisms, underlying detrimental neurodevelopmental consequences induced by early-life alterations of 5-HT levels.
前额叶皮质（PFC）在高级认知功能和情绪行为中起关键作用，且PFC的改变与包括重度抑郁症和焦虑症在内的不同脑部疾病相关。在小鼠中，出生后的前两周是对环境变化高度敏感的关键时期。在这个时间窗口内，血清素（5-HT）水平调节PFC皮质神经元的布线。早期生活中的不良刺激以及出生后接触选择性血清素再摄取抑制剂氟西汀（FLX）会影响PFC发育，导致成年小鼠出现抑郁和焦虑样表型。然而，导致这些功能障碍的机制仍不清楚。我们发现，出生后早期接触FLX（PNFLX）会导致成年雌雄小鼠体内内侧PFC深层假定锥体神经元（PNs）的总体放电和高频爆发减少。在体外，膜片钳记录显示，PNFLX消除了深层mPFC PNs中一个独特亚群的高频放电，这些神经元在出生后的前两周短暂表达血清素转运体SERT。SERT+和SERT- PNs表现出不同的形态功能特性。5-HT7Rs的基因缺失和药理学上的5-HT7R阻断部分挽救了PNFLX诱导的体内PN放电减少以及体外SERT+ PNs放电改变。这表明该5-羟色胺受体亚型在介导易受早期生活不良刺激影响的PFC回路的5-羟色胺依赖性成熟中起关键作用。总体而言，我们的结果提示了潜在的新神经生物学机制，这些机制是5-羟色胺水平早期改变所导致的有害神经发育后果的基础。
