Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Schizophr Bull. 2024 Jan 1;50(1):210-223. doi: 10.1093/schbul/sbad123.
Consistent with postmortem findings in patients, most animal models for schizophrenia (SCZ) present abnormal levels of parvalbumin (PV), a marker of fast-spiking GABAergic interneurons, in the prefrontal cortex (PFC) and hippocampus (HIP). However, there are discrepancies in the literature. PV reductions lead to a functional loss of PV interneurons, which is proposed to underly SCZ symptoms. Given its complex etiology, different categories of animal models have been developed to study SCZ, which may distinctly impact PV levels in rodent brain areas.
We performed a quantitative meta-analysis on PV-positive cell number/density and expression levels in the PFC and HIP of animal models for SCZ based on pharmacological, neurodevelopmental, and genetic manipulations.
Our results confirmed that PV levels are significantly reduced in the PFC and HIP regardless of the animal model. By categorizing into subgroups, we found that all pharmacological models based on NMDA receptor antagonism decreased PV-positive cell number/density or PV expression levels in both brain areas examined. In neurodevelopmental models, abnormal PV levels were confirmed in both brain areas in maternal immune activation models and HIP of the methylazoxymethanol acetate model. In genetic models, negative effects were found in neuregulin 1 and ERBB4 mutant mice in both brain regions and the PFC of dysbindin mutant mice. Regarding sex differences, male rodents exhibited PV reductions in both brain regions only in pharmacological models, while few studies have been conducted in females.
Overall, our findings support deficits in prefrontal and hippocampal PV interneurons in animal models for SCZ.
与患者的尸检结果一致，大多数精神分裂症（SCZ）动物模型在前额叶皮层（PFC）和海马体（HIP）中表现出异常水平的钙结合蛋白（PV），这是一种快速发射 GABA 能中间神经元的标志物。然而，文献中存在差异。PV 减少导致 PV 中间神经元的功能丧失，这被认为是 SCZ 症状的基础。鉴于其复杂的病因，已经开发出不同类别的动物模型来研究 SCZ，这可能会明显影响啮齿动物大脑区域的 PV 水平。
我们基于药理学、神经发育和遗传操作，对 SCZ 动物模型的 PFC 和 HIP 中的 PV 阳性细胞数量/密度和表达水平进行了定量荟萃分析。
我们的结果证实，无论动物模型如何，PV 水平在前额叶皮层和海马体中均显著降低。通过分类成亚组，我们发现所有基于 NMDA 受体拮抗作用的药理学模型都降低了这两个大脑区域中 PV 阳性细胞数量/密度或 PV 表达水平。在神经发育模型中，在母体免疫激活模型和醋酸甲基苯氧乙胺模型的 HIP 中，都证实了异常的 PV 水平。在遗传模型中，在神经调节蛋白 1 和 ERBB4 突变小鼠中，在两个大脑区域和 dysbindin 突变小鼠的 PFC 中都发现了负效应。关于性别差异，只有在药理学模型中，雄性啮齿动物在前额叶皮层和海马体中都表现出 PV 减少，而在雌性中进行的研究较少。
总体而言，我们的研究结果支持 SCZ 动物模型中前额叶和海马体 PV 中间神经元的缺陷。
