Background

Impairment of specific cognitive domains in schizophrenia has been associated with prefrontal cortex (PFC) catecholaminergic deficits. Among other factors, prenatal exposure to infections represents an environmental risk factor for schizophrenia development in adulthood. However, it remains largely unknown whether the prenatal infection-induced changes in the brain may be associated with concrete switches in a particular neurochemical circuit, and therefore, if they could alter behavioral functions.

Methods

In vitro and in vivo neurochemical evaluation of the PFC catecholaminergic systems was performed in offspring from mice undergoing maternal immune activation (MIA). The cognitive status was also evaluated. Prenatal viral infection was mimicked by polyriboinosinic-polyribocytidylic acid (poly(I:C)) administration to pregnant dams (7.5 mg/kg i.p., gestational day 9.5) and consequences were evaluated in adult offspring.

Results

MIA-treated offspring showed disrupted recognition memory in the novel object recognition task (t = 2.30, p = 0.031). This poly(I:C)-based group displayed decreased extracellular dopamine (DA) concentrations compared to controls (t = 3.17, p = 0.0068). Potassium-evoked release of DA and noradrenaline (NA) were impaired in the poly(I:C) group (DA: F_t[10,90] = 43.33, p < 0.0001; F_tr[1,90] = 1.224, p = 0.2972; F_i[10,90] = 5.916, p < 0.0001; n = 11); (NA: F_t[10,90] = 36.27, p < 0.0001; F_tr[1,90] = 1.841, p = 0.208; F_i[10,90] = 8.686, p < 0.0001; n = 11). In the same way, amphetamine‐evoked release of DA and NA were also impaired in the poly(I:C) group (DA: F_t[8,328] = 22.01, p < 0.0001; F_tr[1,328] = 4.507, p = 0.040; F_i[8,328] = 2.319, p = 0.020; n = 43); (NA: F_t[8,328] = 52.07; p < 0.0001; F_tr[1,328] = 4.322; p = 0.044; F_i[8,398] = 5.727; p < 0.0001; n = 43). This catecholamine imbalance was accompanied by increased dopamine D₁ and D₂ receptor expression (t = 2.64, p = 0.011 and t = 3.55, p = 0.0009; respectively), whereas tyrosine hydroxylase, DA and NA tissue content, DA and NA transporter (DAT/NET) expression and function were unaltered.

Conclusions

MIA induces in offspring a presynaptic catecholaminergic hypofunction in PFC with cognitive impairment. This poly(I:C)-based model reproduces catecholamine phenotypes reported in schizophrenia and represents an opportunity for the study of cognitive impairment associated to this disorder.

中文翻译：

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母体免疫激活导致后代皮质儿茶酚胺能功能减退和认知障碍

背景

精神分裂症中特定认知域的损害与前额皮质（PFC）儿茶酚胺能缺陷有关。除其他因素外，产前接触感染是成年后患精神分裂症的一个环境危险因素。然而，目前尚不清楚产前感染引起的大脑变化是否与特定神经化学回路中的具体开关有关，以及它们是否会改变行为功能。

方法

对经历母体免疫激活 (MIA) 的小鼠后代进行 PFC 儿茶酚胺能系统的体外和体内神经化学评估。还评估了认知状态。通过向怀孕母鼠注射聚核糖肌苷-聚核糖胞苷酸（聚（I：C））（腹腔注射7.5毫克/千克，妊娠第9.5天）来模拟产前病毒感染，并在成年后代中评估后果。

结果

经过 MIA 处理的后代在新物体识别任务中表现出识别记忆中断（t  = 2.30，p  = 0.031）。与对照组相比，基于聚 (I:C) 的组显示出细胞外多巴胺 (DA) 浓度降低 ( t  = 3.17，p  = 0.0068)。聚 (I:C) 组中钾诱发的 DA 和去甲肾上腺素 (NA) 释放受损（DA：F _t [10,90] = 43.33，p  < 0.0001；F _tr [1,90] = 1.224，p  = 0.2972；F _i [10,90] = 5.916，p  < 0.0001；n = 11)；（NA：F _t [10,90] = 36.27，p  < 0.0001；F _tr [1,90] = 1.841，p  = 0.208；F _i [10,90] = 8.686，p  < 0.0001；n = 11）。同样，聚（I:C）组中苯丙胺诱发的 DA 和 NA 释放也受到损害（DA：F _t [8,328] = 22.01，p  < 0.0001；F _tr [1,328] = 4.507，p  = 0.040；F _i [8,328] = 2.319，p  = 0.020；n = 43)；（NA：F _t [8,328] = 52.07；p  < 0.0001；F _tr [1,328] = 4.322；p  = 0.044；Fi _[ 8,398] = 5.727；p  < 0.0001；n = 43）。这种儿茶酚胺失衡伴随着多巴胺 D ₁和 D ₂受体表达增加（分别为t  = 2.64，p  = 0.011 和t  = 3.55，p  = 0.0009），而酪氨酸羟化酶、DA 和 NA 组织含量、DA 和 NA 转运蛋白（分别为 t = 2.64，p = 0.011 和 t = 3.55，p = 0.0009） DAT/NET) 表达和功能未改变。

结论

MIA 会导致后代 PFC 突触前儿茶酚胺能功能减退，并伴有认知障碍。这种基于聚（I:C）的模型再现了精神分裂症中报道的儿茶酚胺表型，并为研究与这种疾病相关的认知障碍提供了机会。