Santoni Michele, Frau Roberto, Pistis Marco
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.
"Guy Everett" Laboratory, University of Cagliari, Cagliari, Italy.
Front Pharmacol. 2022 Feb 8;13:821498. doi: 10.3389/fphar.2022.821498. eCollection 2022.
Several epidemiological studies suggest an association between maternal infections during pregnancy and the emergence of neurodevelopmental disorders in the offspring, such as autism and schizophrenia. Animal models broadened the knowledge about the pathophysiological mechanisms that develop from prenatal infection to the onset of psychopathological phenotype. Mounting evidence supports the hypothesis that detrimental effects of maternal immune activation might be transmitted across generations. Here, we explored the transgenerational effects on the dopamine system of a maternal immune activation model based on the viral mimetic polyriboinosinic-polyribocytidilic acid. We assessed dopamine neurons activity in the ventral tegmental area by electrophysiology. Furthermore, we studied two behavioral tests strictly modulated by the mesolimbic dopamine system, i.e., the open field in response to amphetamine and the prepulse inhibition of the startle reflex in response to the D2 agonist apomorphine. Second-generation adult male rats did not display any deficit in sensorimotor gating; however, they displayed an altered activity of ventral tegmental area dopamine neurons, indexed by a reduced spontaneous firing rate and a heightened motor activation in response to amphetamine administration in the open field. On the other hand, second-generation female rats were protected from ancestors' polyriboinosinic-polyribocytidilic acid treatment, as they did not show any alteration in dopamine cell activity or in behavioral tests. These results confirm that maternal immune activation negatively influences, in a sex-dependent manner, neurodevelopmental trajectories of the dopamine system across generations.
多项流行病学研究表明，孕期母体感染与后代神经发育障碍（如自闭症和精神分裂症）的出现之间存在关联。动物模型拓宽了我们对从产前感染到精神病理表型发作所涉及的病理生理机制的认识。越来越多的证据支持母体免疫激活的有害影响可能会跨代传播这一假说。在此，我们基于病毒模拟物聚肌苷酸 - 聚胞苷酸，探究了母体免疫激活模型对多巴胺系统的跨代影响。我们通过电生理学评估腹侧被盖区多巴胺神经元的活性。此外，我们研究了两种严格受中脑边缘多巴胺系统调节的行为测试，即对苯丙胺的旷场反应以及对D2激动剂阿扑吗啡的惊吓反射前脉冲抑制。第二代成年雄性大鼠在感觉运动门控方面未表现出任何缺陷；然而，它们腹侧被盖区多巴胺神经元的活性发生了改变，表现为自发放电率降低以及在旷场中对苯丙胺给药的运动激活增强。另一方面，第二代雌性大鼠未受祖先聚肌苷酸 - 聚胞苷酸处理的影响，因为它们在多巴胺细胞活性或行为测试中均未表现出任何改变。这些结果证实，母体免疫激活以性别依赖的方式对多巴胺系统的跨代神经发育轨迹产生负面影响。
