Glausier Jill R, Lewis David A
Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States.
Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States.
Handb Clin Neurol. 2018;150:389-417. doi: 10.1016/B978-0-444-63639-3.00025-6.
Schizophrenia is a complex disorder lacking an effective treatment option for the pervasive and debilitating cognitive impairments experienced by patients. Working memory is a core cognitive function impaired in schizophrenia that depends upon activation of distributed neural network, including the circuitry of the dorsolateral prefrontal cortex (DLPFC). Accordingly, individuals diagnosed with schizophrenia show reduced DLPFC activation while performing working-memory tasks. This lower DLPFC activation appears to be an integral part of the disease pathophysiology, and not simply a reflection of poor performance. Thus, the cellular and circuitry alterations that underlie lower DLPFC neuronal activity in schizophrenia must be determined in order to identify appropriate therapeutic targets. Studies using human postmortem brain tissue provide a robust way to investigate and characterize these cellular and circuitry alterations at multiple levels of resolution, and such studies provide essential information that cannot be obtained either through in vivo studies in humans or through experimental animal models. Studies examining neuronal morphology, protein expression and localization, and transcript levels indicate that a microcircuit composed of excitatory pyramidal cells and inhibitory interneurons containing the calcium-binding protein parvalbumin is altered in the DLPFC of subjects with schizophrenia and likely contributes to DLPFC dysfunction.
精神分裂症是一种复杂的疾病，对于患者所经历的普遍且使人衰弱的认知障碍，目前缺乏有效的治疗方法。工作记忆是精神分裂症中受损的一项核心认知功能，它依赖于包括背外侧前额叶皮质（DLPFC）回路在内的分布式神经网络的激活。因此，被诊断为精神分裂症的个体在执行工作记忆任务时，DLPFC的激活会减少。这种较低的DLPFC激活似乎是疾病病理生理学的一个组成部分，而不仅仅是表现不佳的反映。因此，必须确定精神分裂症中DLPFC神经元活动较低的细胞和回路改变，以便确定合适的治疗靶点。使用人类尸检脑组织的研究提供了一种强有力的方法，可以在多个分辨率水平上研究和表征这些细胞和回路改变，并且此类研究提供了通过人类体内研究或实验动物模型无法获得的重要信息。研究神经元形态、蛋白质表达和定位以及转录水平表明，在精神分裂症患者的DLPFC中，由兴奋性锥体细胞和含有钙结合蛋白小白蛋白的抑制性中间神经元组成的微回路发生了改变，这可能导致DLPFC功能障碍。
