Arnold S E, Han L Y, Moberg P J, Turetsky B I, Gur R E, Trojanowski J Q, Hahn C G
Center for Neurobiology and Behavior, University of Pennsylvania, 142 Clinical Research Bldg, 415 Curie Blvd, Philadelphia, PA 19104, USA.
Arch Gen Psychiatry. 2001 Sep;58(9):829-35. doi: 10.1001/archpsyc.58.9.829.
Growing evidence implicates abnormal neurodevelopment in schizophrenia. While neuron birth and differentiation is largely completed by the end of gestation, the olfactory epithelium (OE) is a unique part of the central nervous system that undergoes regeneration throughout life, thus offering an opportunity to investigate cellular and molecular events of neurogenesis and development postmortem. We hypothesized that OE neurons exhibit deviant progress through neurodevelopment in schizophrenia characterized by an increase in immature neurons.
Olfactory epithelium was removed at autopsy from 13 prospectively assessed elderly subjects who had schizophrenia and 10 nonpsychiatric control subjects. Sections were immunolabeled with antibodies that distinguish OE neurons in different stages of development, including basal cells (low-affinity nerve growth factor receptor, p75NGFR), postmitotic immature neurons (growth-associated protein 43 [GAP43]), and mature olfactory receptor neurons (olfactory marker protein). Absolute and relative densities of each cell type were determined.
We observed a significantly lower density of p75NGFR basal cells (37%) in schizophrenia and increases in GAP43 + postmitotic immature neurons (316%) and ratios of GAP43 + postmitotic immature neurons to p75NGFR + cells (665%) and olfactory marker protein + mature neurons to p75NGFR + basal cells (328%). Neuroleptic-free schizophrenia subjects exhibited the highest GAP43 + postmitotic immature neuron values.
Abnormal densities and ratios of OE neurons at different stages of development indicate dysregulation of OE neuronal lineage in schizophrenia. This could be because of intrinsic factors controlling differentiation or an inability to gain trophic support from axonal targets in the olfactory bulb. While caution is necessary in extrapolating developmental findings in mature OE to early brain development, similarities in molecular events suggest that such studies may be instructive.
越来越多的证据表明精神分裂症存在异常神经发育。虽然神经元的生成和分化在妊娠末期基本完成，但嗅上皮（OE）是中枢神经系统的一个独特部分，其在整个生命过程中都会进行再生，因此为死后研究神经发生和发育的细胞及分子事件提供了一个机会。我们假设，在精神分裂症中，嗅上皮神经元在神经发育过程中表现出异常进展，其特征为未成熟神经元增加。
对13例经前瞻性评估的老年精神分裂症患者和10例非精神疾病对照者进行尸检时取下嗅上皮。切片用抗体进行免疫标记，这些抗体可区分处于不同发育阶段的嗅上皮神经元，包括基底细胞（低亲和力神经生长因子受体，p75NGFR）、有丝分裂后未成熟神经元（生长相关蛋白43 [GAP43]）和成熟嗅觉受体神经元（嗅觉标记蛋白）。测定每种细胞类型的绝对密度和相对密度。
我们观察到，精神分裂症患者中p75NGFR基底细胞的密度显著降低（37%），GAP43 + 有丝分裂后未成熟神经元增加（316%），GAP43 + 有丝分裂后未成熟神经元与p75NGFR + 细胞的比例增加（665%），嗅觉标记蛋白 + 成熟神经元与p75NGFR + 基底细胞的比例增加（328%）。未服用抗精神病药物的精神分裂症患者的GAP43 + 有丝分裂后未成熟神经元值最高。
不同发育阶段嗅上皮神经元的密度和比例异常表明精神分裂症中嗅上皮神经元谱系失调。这可能是由于控制分化的内在因素，或者是无法从嗅球的轴突靶点获得营养支持。虽然将成熟嗅上皮中的发育研究结果外推至早期脑发育时需要谨慎，但分子事件的相似性表明此类研究可能具有指导意义。
