Volk D W, Lewis D A
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, United States.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, United States; Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, United States.
Neuroscience. 2013 Sep 17;248:154-64. doi: 10.1016/j.neuroscience.2013.06.008. Epub 2013 Jun 14.
Cognitive deficits in schizophrenia have been linked to disturbances in GABA neurons in the prefrontal cortex (PFC). Furthermore, cognitive deficits in schizophrenia appear well before the onset of psychosis and have been reported to be present during early childhood and even during the first year of life. Taken together, these data raise the following question: Does the disease process that produces abnormalities in prefrontal GABA neurons in schizophrenia begin prenatally and disrupt the ontogeny of cortical GABA neurons? Here, we address this question through a consideration of evidence that genetic and/or environmental insults that occur during gestation initiate a pathogenetic process that alters cortical GABA neuron ontogeny and produces the pattern of GABA neuron abnormalities, and consequently cognitive difficulties, seen in schizophrenia. First, we review available evidence from postmortem human brain tissue studies characterizing alterations in certain subpopulations of prefrontal GABA neuron that provide clues to a prenatal origin in schizophrenia. Second, we review recent discoveries of transcription factors, cytokine receptors, and other developmental regulators that govern the birth, migration, specification, maturation, and survival of different subpopulations of prefrontal GABA neurons. Third, we discuss recent studies demonstrating altered expression of these ontogenetic factors in the PFC in schizophrenia. Fourth, we discuss the potential role of disturbances in the maternal-fetal environment such as maternal immune activation in the development of GABA neuron dysfunction. Finally, we propose critical questions that need to be answered in future research to further investigate the role of altered GABA neuron ontogeny in the pathogenesis of schizophrenia.
精神分裂症的认知缺陷与前额叶皮质（PFC）中γ-氨基丁酸（GABA）能神经元的紊乱有关。此外，精神分裂症的认知缺陷在精神病发作之前就已出现，据报道在幼儿期甚至生命的第一年就已存在。综合这些数据，提出了以下问题：导致精神分裂症前额叶GABA能神经元异常的疾病过程是否始于产前并扰乱皮质GABA能神经元的个体发生？在这里，我们通过考虑以下证据来解决这个问题：妊娠期间发生的遗传和/或环境损伤引发了一个致病过程，该过程改变了皮质GABA能神经元的个体发生，并产生了精神分裂症中所见的GABA能神经元异常模式，进而导致认知困难。首先，我们回顾了来自死后人类脑组织研究的现有证据，这些证据描述了前额叶GABA能神经元某些亚群的改变，为精神分裂症的产前起源提供了线索。其次，我们回顾了最近发现的转录因子、细胞因子受体和其他发育调节因子，这些因子控制着前额叶GABA能神经元不同亚群的产生、迁移、特化、成熟和存活。第三，我们讨论了最近的研究，这些研究表明精神分裂症患者前额叶皮质中这些个体发生因子的表达发生了改变。第四，我们讨论了母胎环境紊乱，如母体免疫激活在GABA能神经元功能障碍发展中的潜在作用。最后，我们提出了未来研究中需要回答的关键问题，以进一步探讨GABA能神经元个体发生改变在精神分裂症发病机制中的作用。
