Di Bartolomeo Martina, Aroni Sonia, Serra Marcello, Serra Valeria, Martella Francesca, Gilardini Federica, Melis Miriam, D'Addario Claudio
Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, 64100 Teramo, Italy.
Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09100 Cagliari, Italy.
Cells. 2025 Jun 14;14(12):904. doi: 10.3390/cells14120904.
Prenatal cannabis exposure (PCE) has been associated with altered prefrontal cortex (PFC) activity and connectivity in adulthood, potentially increasing the risk of psychopathology later in life. This risk is thought to involve a complex interplay between the endocannabinoid and dopaminergic systems. We investigated the transcriptional regulation of genes associated with these systems in an animal model of PCE during adolescence, focusing on DNA methylation and specific microRNAs (miRNAs). Our study revealed increased mRNA levels of dopamine D1 and D2 receptors ( and ) in the PFC, with a notable effect on in male offspring. Notably, we observed a consistent reduction in DNA methylation levels in PCE male rats. Both and expressions were regulated by selective miRNAs. Accordingly, we found changes in the excitability of PFC pyramidal neurons in male adolescent PCE offspring, along with alterations in the Netrin-1/DCC guidance cue system. Our findings highlight PCE-induced modifications of the PFC dopaminergic system while maintaining stable gene expression of the endocannabinoid system in male offspring. Changes in this complex interaction during sensitive developmental periods like adolescence might lead to sex-dependent divergent behavioral outcomes induced by PCE.
产前大麻暴露（PCE）与成年期前额叶皮质（PFC）活动和连接性改变有关，可能会增加日后患精神病理学的风险。这种风险被认为涉及内源性大麻素系统和多巴胺能系统之间的复杂相互作用。我们在青少年期PCE的动物模型中研究了与这些系统相关基因的转录调控，重点关注DNA甲基化和特定的微小RNA（miRNA）。我们的研究揭示了PFC中多巴胺D1和D2受体（ 和 ）的mRNA水平升高，对雄性后代的 有显著影响。值得注意的是，我们观察到PCE雄性大鼠 的DNA甲基化水平持续降低。 和 的表达均受选择性miRNA调控。因此，我们发现雄性青少年PCE后代的PFC锥体神经元兴奋性发生变化，同时Netrin-1/DCC导向信号系统也发生改变。我们的研究结果突出了PCE对雄性后代PFC多巴胺能系统的诱导性修饰，同时维持内源性大麻素系统的稳定基因表达。在青春期等敏感发育阶段，这种复杂相互作用的变化可能导致PCE诱导的性别依赖性行为差异。
