Influence of DISC1 genetics on brain and behavioral development of offspring exposed to Maternal immune activation

摘要 流行病学数据表明，怀孕期间暴露于感染可能会改变 胎儿大脑发育和增加后代神经发育障碍的风险，包括精神分裂症 （SZ）。母体免疫激活（MIA）的动物模型已经证明， 母体免疫系统和随后的母体细胞因子反应诱导后代脑的变化 以及与人类神经发育障碍相关领域的行为发育。虽然许多母亲 在怀孕期间有免疫挑战，只有这些母亲所生的孩子的一个子集发展 神经发育障碍这暗示了一种潜在的理论，即有些孩子可能天生 易受MIA影响MIA的恢复力和易感性的最重要因素之一可能是遗传， 因为几种疾病表现为遗传易感性和环境风险的相互作用。一个基因 特别感兴趣的是DISC 1（Disrupted-in-schizophrenia-1）基因。DISC 1是在苏格兰的一个大型 与SZ和SZ谱系障碍、双相情感障碍和情绪的发生率较高有关 紊乱已经发现DISC 1对于适当的神经发育是必要的，通过与 胚胎和成人神经发生、突触传递、神经元增殖、皮质发生和突触 阵DISC 1-/-动物模型已被用于表征SZ病理生理学和风险，因为它们模拟了 SZ患者中常见的异常神经发育。DISC 1-/-模型提供了以下机会： 探索环境对MIA结果的影响。DISC 1-/-小鼠暴露于MIA的初步研究 已经开始发现有希望的基因与环境的相互作用。然而，仅仅依靠小鼠模型， 限制了我们评估复杂的社会和认知行为的能力，这两个领域对我们的生活至关重要。 了解SZ相关表型。此外，以前的MIA DISC 1-/-研究没有检查 通过新生儿全脑观察母体免疫应答与子代发育的关系 细胞因子、行为和成人多巴胺D2受体水平。我们提出了一种新的大鼠模型来研究 在表征暴露于LPS诱导的MIA和MIA的大鼠中基因和环境之间的相互作用 DISC 1敲除。成功完成所提出的目标将开始揭示遗传易感性如何可能 塑造MIA后代表型。

Abstract Epidemiological data suggest that exposure to infection during pregnancy may initiate an altered trajectory of fetal brain development and increases risk of offspring neurodevelopmental disorders, including schizophrenia (SZ). Animal models of maternal immune activation (MIA) have demonstrated that experimental activation of the maternal immune system and the subsequent maternal cytokine response induces changes in offspring brain and behavioral development in domains relevant to human neurodevelopmental disorders. While many mothers have immune challenges during pregnancy, only a subset of the children born to those mothers develop neurodevelopmental disorders. This hints at the potential theory that some children may be inherently susceptible to MIA. One of the most important factors for resilience and susceptibility in MIA may be genetics, as several disorders manifest as an interaction of genetic susceptibility and environmental risk. One gene of particular interest is the DISC1 (Disrupted-in-schizophrenia-1) gene. DISC1 was discovered in large Scottish pedigree and is linked to a higher incidence of SZ and SZ spectrum disorders, bipolar disorder, and mood disorders. DISC1 has been found to be necessary for proper neurodevelopment, through associations with embryonic and adult neurogenesis, synaptic transmission, neuronal proliferation, corticogenesis, and synapse formation. Animal models of DISC1-/- have been used to characterize SZ pathophysiology and risk, as they mimic the aberrant neurodevelopment that is often seen in SZ patients. The DISC1-/- model provides an opportunity to explore gene by environment effects on MIA outcomes. Preliminary studies of DISC1-/- mice exposed to MIA have begun to uncover promising gene by environment interactions. However, relying solely on mouse models limits our ability to evaluate complex social and cognitive behaviors, two areas which are critical for understanding SZ-related phenotypes. In addition, previous MIA DISC1-/- studies have not examined the relationship of the dam’s immune response to the development of the offspring through neonatal whole brain cytokines, behavior, and adult dopamine D2 receptor levels. We propose a novel rat model to investigate the interactions between gene and environment in characterizing rats exposed to both LPS-induced MIA and the DISC1 knockout. Successful completion of the proposed aims will begin uncover how genetic susceptibility may shape MIA offspring phenotypes.