In neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD) and schizophrenia, impairment/malfunctioning of a subpopulation of interneurons expressing the calcium-binding protein parvalbumin (PV) –here termed Pvalb neurons– has gradually emerged as a possible cause. These neurons may represent a hub or point-of-convergence in the etiology of NDD. Increased oxidative stress associated with mitochondria impairment in Pvalb neurons is discussed as an essential step in schizophrenia etiology. Since PV downregulation is a common finding in ASD and schizophrenia individuals and PV-deficient (PV−/−) mice show a strong ASD-like behavior phenotype, we investigated the putative link between PV expression, alterations in mitochondria and oxidative stress. In a longitudinal study with 1, 3, and 6-months old PV−/− and wild type mice, oxidative stress was investigated in 9 Pvalb neuron subpopulations in the hippocampus, striatum, somatosensory cortex, medial prefrontal cortex, thalamic reticular nucleus (TRN) and cerebellum. In Pvalb neuron somata in the striatum and TRN, we additionally determined mitochondria volume and distribution at these three time points. In all Pvalb neuron subpopulations, we observed an age-dependent increase in oxidative stress and the increase strongly correlated with PV expression levels, but not with mitochondria density in these Pvalb neurons. Moreover, oxidative stress was elevated in Pvalb neurons of PV−/− mice and the magnitude of the effect was again correlated with PV expression levels in the corresponding wild type Pvalb neuron subpopulations. The PV-dependent effect was insignificant at 1 month and relative differences between WT and PV−/− Pvalb neurons were largest at 3 months. Besides the increase in mitochondria volume in PV’s absence in TRN and striatal PV−/− Pvalb neurons fully present already at 1 month, we observed a redistribution of mitochondria from the perinuclear region toward the plasma membrane at all time points. We suggest that in absence of PV, slow Ca²⁺ buffering normally exerted by PV is compensated by a (mal)adaptive, mostly sub-plasmalemmal increase in mitochondria resulting in increased oxidative stress observed in 3- and 6-months old mice. Since PV−/− mice display core ASD-like symptoms already at 1 month, oxidative stress in Pvalb neurons is not a likely cause for their ASD-related behavior observed at this age.

在包括自闭症谱系障碍 (ASD) 和精神分裂症在内的神经发育障碍 (NDD) 中，表达钙结合蛋白小白蛋白 (PV) 的中间神经元亚群（此处称为 Pvalb 神经元）的损伤/功能障碍已逐渐成为可能的原因。这些神经元可能代表 NDD 病因学的枢纽或汇聚点。与 Pvalb 神经元线粒体损伤相关的氧化应激增加被讨论为精神分裂症病因学的一个重要步骤。由于 PV 下调是自闭症谱系障碍 (ASD) 和精神分裂症患者中的常见现象，并且 PV 缺陷 (PV−/−) 小鼠表现出强烈的 ASD 样行为表型，因此我们研究了 PV 表达、线粒体改变和氧化应激之间的假定联系。在一项针对 1、3 和 6 个月大的 PV−/− 和野生型小鼠的纵向研究中，对海马、纹状体、体感皮层、内侧前额皮质、丘脑网状核 (TRN) 的 9 个 Pvalb 神经元亚群的氧化应激进行了研究）和小脑。在纹状体和 TRN 的 Pvalb 神经元体细胞中，我们还确定了这三个时间点的线粒体体积和分布。在所有 Pvalb 神经元亚群中，我们观察到氧化应激呈年龄依赖性增加，并且这种增加与 PV 表达水平密切相关，但与这些 Pvalb 神经元中的线粒体密度无关。此外，PV−/− 小鼠的 Pvalb 神经元中的氧化应激水平升高，其影响程度再次与相应野生型 Pvalb 神经元亚群中的 PV 表达水平相关。PV 依赖性效应在 1 个月时不显着，WT 和 PV−/− Pvalb 神经元之间的相对差异在 3 个月时最大。除了 TRN 中 PV 缺失和纹状体 PV−/− Pvalb 神经元在 1 个月时完全存在的 PV 线粒体体积增加之外，我们在所有时间点都观察到线粒体从核周区域向质膜重新分布。我们认为，在没有 PV 的情况下，通常由 PV 发挥的缓慢 Ca ²⁺缓冲通过线粒体的（不良）适应性（主要是亚质膜增加）来补偿，导致在 3 个月和 6 个月大的小鼠中观察到氧化应激增加。由于 PV−/− 小鼠在 1 个月时就已经表现出类似 ASD 的核心症状，因此 Pvalb 神经元中的氧化应激不太可能是其在该年龄观察到的 ASD 相关行为的原因。