OLFACTORY NEURODEVELOPMENTAL PATHOLOGY IN SCHIZOPHRENIA

来自临床和尸检研究的越来越多的证据表明，精神分裂症的病理生理学中存在神经发育异常。虽然神经元的出生、迁移、分化和连接在妊娠结束时基本在中枢神经系统的所有部分完成，但嗅觉上皮和嗅球是独一无二的，因为它们在整个生命过程中经历了持续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，即使是在生命的晚期。此外，嗅皮层的细胞结构异常提示发育异常，尽管研究结果仍有争议。精神分裂症患者在气味检测、识别和记忆方面的明显障碍进一步强调了检查精神分裂症嗅觉系统的重要性。这项拟议的研究将描述人类嗅觉上皮、嗅球和初级嗅觉皮质的神经发育过程，研究对象为特征良好的精神分裂症患者和匹配的对照组。我们的主要假设是，在精神分裂症的嗅觉区域，分子、细胞和连接神经发育的异常模式是明显的。在嗅觉上皮(AIM 1)中，将使用细胞类型特异性抗体和计算机辅助显微镜的免疫组织化学方法来确定嗅觉感受器神经元谱系中分化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素介导的信号转导至关重要的多肽的表达。在嗅球(AIM 2)中，在对突触素、酪氨酸羟基酶、钙视黄素、Calbindin D28k、NCAMs和GAP-43进行免疫标记后，将对肾小球的细胞、树突和轴突成分进行量化。在目标3中，我们将对梨状皮质和内嗅皮层进行定量的细胞构筑分析。将确定免疫组织化学不同神经元群体的相对密度，并将使用空间点模式分析来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.