Santoni Michele, Sagheddu Claudia, Serra Valeria, Mostallino Rafaela, Castelli Maria Paola, Pisano Francesco, Scherma Maria, Fadda Paola, Muntoni Anna Lisa, Zamberletti Erica, Rubino Tiziana, Melis Miriam, Pistis Marco
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy; Neuroscience Institute, Section of Cagliari, National Research Council of Italy (CNR), Cagliari, Italy.
Brain Behav Immun. 2023 Mar;109:271-284. doi: 10.1016/j.bbi.2023.02.002. Epub 2023 Feb 4.
Prenatal infections can increase the risk of developing psychiatric disorders such as schizophrenia in the offspring, especially when combined with other postnatal insults. Here, we tested, in a rat model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid, whether maternal immune activation (MIA) affects the endocannabinoid system and endocannabinoid-mediated modulation of dopamine functions. Experiments were performed during adolescence to assess i) the behavioral endophenotype (locomotor activity, plus maze, prepulse inhibition of startle reflex); ii) the locomotor activity in response to Δ9-Tetrahydrocannabinol (THC) and iii) the properties of ventral tegmental area (VTA) dopamine neurons in vivo and their response to THC; iv) endocannabinoid-mediated synaptic plasticity in VTA dopamine neurons; v) the expression of cannabinoid receptors and enzymes involved in endocannabinoid synthesis and catabolism in mesolimbic structures and vi) MIA-induced neuroinflammatory scenario evaluated by measurements of levels of cytokine and neuroinflammation markers. We revealed that MIA offspring displayed an altered locomotor activity in response to THC, a higher bursting activity of VTA dopamine neurons and a lack of response to cumulative doses of THC. Consistently, MIA adolescence offspring showed an enhanced 2-arachidonoylglycerol-mediated synaptic plasticity and decreased monoacylglycerol lipase activity in mesolimbic structures. Moreover, they displayed a higher expression of cyclooxygenase 2 (COX-2) and ionized calcium-binding adaptor molecule 1 (IBA-1), associated with latent inflammation and persistent microglia activity. In conclusion, we unveiled neurobiological mechanisms whereby inflammation caused by MIA influences the proper development of endocannabinoid signaling that negatively impacts the dopamine system, eventually leading to psychotic-like symptoms in adulthood.
产前感染会增加后代患精神疾病（如精神分裂症）的风险，尤其是在与其他产后损伤因素共同作用时。在此，我们在通过病毒模拟物聚肌苷酸-聚胞苷酸进行产前免疫攻击的大鼠模型中，测试了母体免疫激活（MIA）是否会影响内源性大麻素系统以及内源性大麻素介导的多巴胺功能调节。实验在青春期进行，以评估：i）行为内表型（运动活动、加迷宫实验、惊吓反射的前脉冲抑制）；ii）对Δ9-四氢大麻酚（THC）的运动反应；iii）腹侧被盖区（VTA）多巴胺能神经元在体内的特性及其对THC的反应；iv）VTA多巴胺能神经元中内源性大麻素介导的突触可塑性；v）中脑边缘结构中参与内源性大麻素合成和分解代谢的大麻素受体和酶的表达；vi）通过测量细胞因子和神经炎症标志物水平评估的MIA诱导的神经炎症情况。我们发现，MIA后代对THC的运动反应发生改变，VTA多巴胺能神经元的爆发活动增强，且对累积剂量的THC无反应。一致地，MIA青春期后代在中脑边缘结构中表现出增强的2-花生四烯酸甘油介导的突触可塑性和降低的单酰甘油脂肪酶活性。此外，它们还表现出较高的环氧合酶2（COX-2）和离子钙结合衔接分子1（IBA-1）表达，这与潜在炎症和持续性小胶质细胞活动相关。总之，我们揭示了神经生物学机制，即MIA引起的炎症影响内源性大麻素信号的正常发育，对多巴胺系统产生负面影响，最终导致成年期出现类似精神病的症状。
