Glantz Leisa A, Gilmore John H, Lieberman Jeffrey A, Jarskog L Fredrik
Department of Psychiatry, University of North Carolina-Chapel Hill, CB# 7160, Chapel Hill, NC 27599-7160, USA.
Schizophr Res. 2006 Jan 1;81(1):47-63. doi: 10.1016/j.schres.2005.08.014. Epub 2005 Oct 14.
The cortical neuropathology of schizophrenia includes neuronal atrophy, decreased neuropil, and alterations in neuronal density. Taken together with evidence of decreased synaptic markers and dendritic spines, the data suggest that synaptic circuitry is altered. Recent neuroimaging studies also indicate that a progressive loss of cortical gray matter occurs early in the course of schizophrenia. Although the mechanisms underlying these deficits are largely unknown, recent postmortem data implicate a role for altered neuronal apoptosis. Apoptosis, a form of programmed cell death, is regulated by a complex cascade of pro- and anti-apoptotic proteins. Apoptotic activation can lead to rapid neuronal death. However, emerging data also indicate that sub-lethal apoptotic activity can lead to a limited form of apoptosis in terminal neurites and individual synapses to cause synaptic elimination without cell death. For example, in Alzheimer's disease, a localized apoptotic mechanism is thought to contribute to early neurite and synapse loss leading to the initial cognitive decline. Recent studies indicate that apoptotic regulatory proteins and DNA fragmentation patterns are altered in several cortical regions in schizophrenia. This paper will review converging lines of data that implicate synaptic deficits in the pathophysiology of schizophrenia and propose an underlying role for apoptotic dysregulation.
精神分裂症的皮质神经病理学包括神经元萎缩、神经毡减少以及神经元密度改变。结合突触标记物和树突棘减少的证据来看，这些数据表明突触回路发生了改变。近期的神经影像学研究还表明，皮质灰质在精神分裂症病程早期就开始逐渐丧失。尽管这些缺陷背后的机制大多未知，但最近的尸检数据表明神经元凋亡改变起到了一定作用。凋亡是一种程序性细胞死亡形式，由一系列复杂的促凋亡蛋白和抗凋亡蛋白级联调节。凋亡激活可导致神经元快速死亡。然而，新出现的数据也表明，亚致死性凋亡活动可导致终末神经突和单个突触出现有限形式的凋亡，从而在不导致细胞死亡的情况下引起突触消除。例如，在阿尔茨海默病中，一种局部凋亡机制被认为是导致早期神经突和突触丧失进而引发最初认知衰退的原因。近期研究表明，精神分裂症患者的几个皮质区域中凋亡调节蛋白和DNA片段化模式发生了改变。本文将综述一系列相关数据，这些数据表明突触缺陷在精神分裂症的病理生理学中具有重要意义，并提出凋亡调节异常在其中的潜在作用。
