Department of Psychiatry, Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne, 1008 Prilly-Lausanne, Switzerland.
J Neurosci. 2010 Feb 17;30(7):2547-58. doi: 10.1523/JNEUROSCI.3857-09.2010.
Elevated oxidative stress and alteration in antioxidant systems, including glutathione (GSH) decrease, are observed in schizophrenia. Genetic and functional data indicate that impaired GSH synthesis represents a susceptibility factor for the disorder. Here, we show that a genetically compromised GSH synthesis affects the morphological and functional integrity of hippocampal parvalbumin-immunoreactive (PV-IR) interneurons, known to be affected in schizophrenia. A GSH deficit causes a selective decrease of PV-IR interneurons in CA3 and dendate gyrus (DG) of the ventral but not dorsal hippocampus and a concomitant reduction of beta/gamma oscillations. Impairment of PV-IR interneurons emerges at the end of adolescence/early adulthood as oxidative stress increases or cumulates selectively in CA3 and DG of the ventral hippocampus. Such redox dysregulation alters stress and emotion-related behaviors but leaves spatial abilities intact, indicating functional disruption of the ventral but not dorsal hippocampus. Thus, a GSH deficit affects PV-IR interneuron's integrity and neuronal synchrony in a region- and time-specific manner, leading to behavioral phenotypes related to psychiatric disorders.
氧化应激升高和抗氧化系统改变，包括谷胱甘肽 (GSH) 减少，在精神分裂症中观察到。遗传和功能数据表明，GSH 合成受损代表该疾病的易感性因素。在这里，我们表明，遗传上受损的 GSH 合成会影响海马 CA3 和齿状回 (DG) 中被认为受精神分裂症影响的颗粒蛋白免疫反应性 (PV-IR) 中间神经元的形态和功能完整性。GSH 缺乏会导致腹侧海马 CA3 和 DG 中的 PV-IR 中间神经元选择性减少，同时 beta/gamma 振荡减少。氧化应激增加或选择性累积在腹侧海马 CA3 和 DG 中，在青春期后期/成年早期出现 PV-IR 中间神经元损伤。这种氧化还原失调会改变与应激和情绪相关的行为，但不会影响空间能力，表明腹侧海马而不是背侧海马的功能障碍。因此，GSH 缺乏以区域和时间特异性的方式影响 PV-IR 中间神经元的完整性和神经元同步性，导致与精神疾病相关的行为表型。
