OLFACTORY NEURODEVELOPMENTAL PATHOLOGY IN SCHIZOPHRENIA

越来越多来自临床和尸检研究的证据表明，精神分裂症的病理生理中存在神经发育异常。尽管中枢神经系统几乎所有部位的神经元的诞生、迁移、分化和连接在妊娠结束时基本完成，但嗅上皮和嗅球的独特之处在于它们在整个生命过程中都经历了不断的再生和再神经支配。因此，它们提供了一个机会来研究正在进行的神经元和连接发育的细胞和分子事件，甚至在晚年。此外，细胞结构异常提示异常发育已被描述在嗅觉皮质，尽管结果仍有争议。精神分裂症患者在气味检测、识别和记忆方面的显著损伤进一步强调了检查嗅觉系统的重要性。该研究将在具有良好特征的精神分裂症患者和匹配对照中描述人类嗅上皮、嗅球和初级嗅皮质的神经发育过程。我们的首要假设是，分子、细胞和连接神经发育的异常模式在精神分裂症患者的嗅觉区是明显的。在嗅觉上皮中（Aim 1），将使用细胞类型特异性抗体的免疫组织化学和计算机辅助显微镜来确定嗅觉受体神经元谱系中不同细胞类型的相对比例和形态特征，以及它们对神经元细胞骨架和神经营养因子介导的信号转导很重要的多肽的表达。在嗅球（Aim 2）中，免疫标记synaptophysin、酪氨酸羟化酶、calretinin、calbindin D28k、NCAMs和GAP- 43后，定量测定肾小球的细胞、树突和轴突组成。在Aim 3中，我们将对梨状和内嗅皮质进行定量细胞结构分析。将确定免疫组织化学不同神经元群体的相对密度，并使用空间点模式分析评估神经元的空间排列。

Growing evidence from clinical and postmortem research implicates abnormal neurodevelopment in the pathophysiology of schizophrenia. While neuron birth, migration, differentiation, and connectivity are largely completed by the end of gestation in almost all parts of the CNS, the olfactory epithelium and olfactory bulb are unique in that they undergo continuous regeneration and reinnervation throughout life. Thus, they offer an opportunity to investigate cellular and molecular events of ongoing neuronal and connectional development, even in late life. In addition, cytoarchitectural abnormalities suggestive of abnormal development have been described in olfactory cortices, although findings remain controversial. The importance of examining the olfactory system in schizophrenia is further underscored by the marked impairments in odor detection, identification, and memory that are present in the disorder. The proposed research will characterize neurodevelopmental processes in human olfactory epithelium, olfactory bulb, and primary olfactory cortices in well-characterized individuals with schizophrenia and matched controls. Our overarching hypothesis is that abnormal patterns of molecular, cellular and connectional neurodevelopment are evident in olfactory regions in schizophrenia. In the olfactory epithelium (Aim 1), immunohistochemistry with cell-type-specific antibodies and computer-assisted microscopy will be used to determine the relative proportions and morphologic characteristics of differentiating cell types in the olfactory receptor neuron lineage, as well as their expression of polypeptides that are important for the neuronal cytoskeleton and for neurotrophin mediated signal transduction. In the olfactory bulb (Aim 2), the cellular, dendritic, and axonal composition of the glomerulus will be quantified after immunolabeling for synaptophysin, tyrosine hydroxylase, calretinin, calbindin D28k, NCAMs and GAP- 43. In Aim 3, we will perform a quantitative cytoarchitectural analysis of piriform and entorhinal cortices. The relative densities of immunohistochemically distinct populations of neurons will be determined and the spatial arrangement of neurons will be assessed using spatial point pattern analyses.