Abstract：
Infection during pregnancy is a substantial risk factor for the unborn child to develop autism or schizophrenia later in life, and is thought to be driven by maternal immune activation (MIA). MIA can be modelled by exposing pregnant mice to Polyinosinic: polycytidylic acid (Poly-I:C), a viral mimetic that induces an immune response and recapitulates in the offspring many neurochemical features of ASD and schizophrenia, including altered BDNF-TrkB signalling and disruptions to excitatory/inhibitory balance. Therefore, we hypothesised that a BDNF mimetic, 7,8-Dihydroxyflavone (7,8-DHF), administered prophylactically to the dam may prevent the neurobehavioural sequelae of disruptions induced by MIA. Dams were treated with 7,8-DHF in the drinking water (0.08 mg/ML) from gestational day (GD) 9-20 and were exposed to Poly-I:C at GD17 (20 mg/kg, i.p.). Foetal brains were collected 6 h post Poly-I:C exposure for RT-qPCR analysis of BDNF, cytokine, GABAergic and glutamatergic gene targets. A second adult cohort were tested in a battery of behavioural tests relevant to schizophrenia and the prefrontal cortex and ventral hippocampus dissected for RT-qPCR analysis. Foetal brains exposed to Poly-I:C showed increased IL-6, but reduced expression of Ntrk2 and multiple GABAergic and glutamatergic markers. Anxiety-like behaviour was observed in adult offspring prenatally exposed to poly-I:C, which was accompanied by altered expression of Gria2 in the prefrontal cortex and Gria4 in the ventral hippocampus. While 7-8 DHF normalised the expression of some glutamatergic (Grm5) and GABAergic (Gabra1) genes in Poly-I:C exposed offspring, it also led to substantial alterations in offspring not exposed to Poly-I:C. Furthermore, mice exposed to 7,8-DHF prenatally showed increased pre-pulse inhibition and reduced working memory in adulthood. These data advance understanding of how 7,8-DHF and MIA prenatal exposure impacts genes critical to excitatory/inhibitory pathways and related behaviour.
摘要：
怀孕期间的感染是未出生的孩子在以后的生活中发展为自闭症或精神分裂症的重要风险因素，并且被认为是由母体免疫激活（MIA）驱动的。MIA可以通过将怀孕小鼠暴露于多肌苷酸：多胞苷酸（Poly-I：C）来建模，一种病毒模拟物，可诱导免疫反应并在后代中概括ASD和精神分裂症的许多神经化学特征，包括BDNF-TrkB信号传导的改变和兴奋性/抑制性平衡的破坏。因此,我们假设BDNF模拟物，7,8-二羟基黄酮（7,8-DHF），预防性给予大坝可以预防MIA引起的神经行为后遗症。从妊娠日（GD）9-20开始，用饮用水中的7,8-DHF（0.08mg/mL）处理水坝，并在GD17时暴露于Poly-I：C（20mg/kg，i.p.）。在Poly-I:C暴露后6小时收集胎儿大脑，用于BDNF的RT-qPCR分析，细胞因子,GABA能和谷氨酸能基因靶标。在一系列与精神分裂症相关的行为测试中测试了第二个成人队列，并解剖了前额叶皮质和腹侧海马以进行RT-qPCR分析。暴露于Poly-I：C的胎儿大脑显示IL-6增加，但Ntrk2和多种GABA能和谷氨酸能标记物的表达降低。在产前暴露于poly-I：C的成年后代中观察到焦虑样行为，伴随着前额叶皮层中Gria2和腹侧海马中Gria4的表达改变。虽然7-8DHF使Poly-I：C暴露的后代中一些谷氨酸能（Grm5）和GABA能（Gabra1）基因的表达正常化，它还导致未暴露于Poly-I：C的后代发生实质性变化。此外，产前暴露于7,8-DHF的小鼠在成年期表现出增加的脉冲前抑制和降低的工作记忆。这些数据促进了对7,8-DHF和MIA产前暴露如何影响对兴奋性/抑制性途径和相关行为至关重要的基因的理解。
