Department of Psychiatry, Harvard Medical School, 25 Shattuck St., Boston, MA 02115, USA; Translational Neuroscience Laboratory, McLean Hospital, 115 Mill St., Belmont, MA 02478, USA.
Schizophr Res. 2013 Nov;150(2-3):366-72. doi: 10.1016/j.schres.2013.08.013. Epub 2013 Sep 10.
Emerging evidence points to proteoglycan abnormalities in the pathophysiology of schizophrenia (SZ). In particular, markedly abnormal expression of chondroitin sulfate proteoglycans (CSPGs), key components of the extracellular matrix, was observed in the medial temporal lobe. CSPG functions, including regulation of neuronal differentiation and migration, are highly relevant to the pathophysiology of SZ. CSPGs may exert similar functions in the olfactory epithelium (OE), a continuously regenerating neural tissue that shows cell and molecular abnormalities in SZ. We tested the hypothesis that CSPG expression in OE may be altered in SZ. CSPG-positive cells in postmortem OE from non-psychiatric control (n=9) and SZ (n=10) subjects were counted using computer-assisted light microscopy. 'Cytoplasmic' CSPG (c-CSPG) labeling was detected in sustentacular cells and some olfactory receptor neurons (c-CSPG+ORNs), while 'pericellular' CSPG (p-CSPG) labeling was found in basal cells and some ORNs (p-CSPG+ORNs). Dual labeling for CSPG and markers for mature and immature ORNs suggests that c-CSPG+ORNs correspond to mature ORNs, and p-CSPG+ORNs to immature ORNs. Previous studies in the same cohort demonstrated that densities of mature ORNs were unaltered (Arnold et al., 2001). In the present study, numerical densities of c-CSPG+ORNs were significantly decreased in SZ (p<0.025; 99.32% decrease), suggesting a reduction of CSPG expression in mature ORNs. Previous studies showed a striking increase in the ratios of immature neurons with respect to basal cells. In this study, we find that the ratio of p-CSPG+ORNs/CSPG+basal cells was significantly increased (p=0.03) in SZ, while numerical density changes of p-CSPG+ORNs (110.71% increase) or CSPG+basal cells (53.71% decrease), did not reach statistical significance. Together, these results indicate that CSPG abnormalities are present in the OE of SZ and specifically point to a reduction of CSPG expression in mature ORNs in SZ. Given the role CSPGs play in OE cell differentiation and axon guidance, we suggest that altered CSPG expression may contribute to ORN lineage dysregulation, and olfactory identification abnormalities, observed in SZ.
越来越多的证据表明蛋白聚糖异常参与了精神分裂症的病理生理学过程。特别是，在中颞叶发现了软骨素硫酸蛋白聚糖（CSPG）这种细胞外基质的关键成分的表达明显异常。CSPG 的功能，包括对神经元分化和迁移的调节，与精神分裂症的病理生理学高度相关。CSPG 可能在嗅觉上皮（OE）中发挥类似的功能，OE 是一种持续再生的神经组织，在精神分裂症中表现出细胞和分子异常。我们检验了以下假说：精神分裂症患者的 OE 中 CSPG 的表达可能发生改变。使用计算机辅助的光学显微镜，对来自非精神疾病对照组（n=9）和精神分裂症组（n=10）的尸检 OE 中的 CSPG 阳性细胞进行计数。在支持细胞和一些嗅受体神经元中检测到“细胞质”CSPG（c-CSPG）标记（c-CSPG+ORNs），而在基底细胞和一些 ORNs 中检测到“细胞周”CSPG（p-CSPG）标记（p-CSPG+ORNs）。CSPG 与成熟和未成熟 ORNs 标志物的双重标记表明，c-CSPG+ORNs 对应于成熟 ORNs，p-CSPG+ORNs 对应于未成熟 ORNs。同一队列的先前研究表明，成熟 ORNs 的密度没有改变（Arnold 等人，2001）。在本研究中，精神分裂症患者的 c-CSPG+ORNs 数量显著减少（p<0.025；减少 99.32%），表明成熟 ORNs 中 CSPG 表达减少。先前的研究表明，未成熟神经元与基底细胞的比例显著增加。在这项研究中，我们发现 p-CSPG+ORNs/CSPG+基底细胞的比值在精神分裂症患者中显著增加（p=0.03），而 p-CSPG+ORNs 的数量密度变化（增加 110.71%）或 CSPG+基底细胞（减少 53.71%）则没有达到统计学意义。总之，这些结果表明，CSPG 异常存在于精神分裂症患者的 OE 中，特别是在精神分裂症患者的成熟 ORNs 中 CSPG 表达减少。鉴于 CSPGs 在 OE 细胞分化和轴突导向中的作用，我们认为改变的 CSPG 表达可能导致 ORN 谱系失调，并导致精神分裂症患者的嗅觉识别异常。
