Institute of Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Center for Systems Neuroscience Hannover (ZSN), 30559 Hannover, Germany.
Institute of Cellular Chemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Development. 2014 Aug;141(15):3022-32. doi: 10.1242/dev.111773. Epub 2014 Jul 3.
Polysialic acid (polySia) is a unique glycan modification of the neural cell adhesion molecule NCAM and a major determinant of brain development. Polysialylation of NCAM is implemented by the two polysialyltransferases (polySTs) ST8SIA2 and ST8SIA4. Dysregulation of the polySia-NCAM system and variation in ST8SIA2 has been linked to schizophrenia and other psychiatric disorders. Here, we show reduced interneuron densities in the medial prefrontal cortex (mPFC) of mice with either partial or complete loss of polySia synthesizing capacity by ablation of St8sia2, St8sia4, or both. Cells positive for parvalbumin and perineuronal nets as well as somatostatin-positive cells were reduced in the mPFC of all polyST-deficient lines, whereas calretinin-positive cells and the parvalbumin-negative fraction of calbindin-positive cells were unaffected. Reduced interneuron numbers were corroborated by analyzing polyST-deficient GAD67-GFP knock-in mice. The accumulation of precursors in the ganglionic eminences and reduced numbers of tangentially migrating interneurons in the pallium were observed in polyST-deficient embryos. Removal of polySia by endosialidase treatment of organotypic slice cultures led to decreased entry of GAD67-GFP-positive interneurons from the ganglionic eminences into the pallium. Moreover, the acute loss of polySia caused significant reductions in interneuron velocity and leading process length. Thus, attenuation of polySia interferes with the developmental migration of cortical interneurons and causes pathological changes in specific interneuron subtypes. This provides a possible link between genetic variation in polyST genes, neurodevelopmental alterations and interneuron dysfunction in neuropsychiatric disease.
唾液酸化多醣（polySia）是神经细胞黏附分子 NCAM 的一种独特糖基修饰，也是大脑发育的主要决定因素。NCAM 的多醣化由两个多醣基转移酶（polySTs）ST8SIA2 和 ST8SIA4 执行。多醣化 NCAM 系统的失调和 ST8SIA2 的变异与精神分裂症和其他精神疾病有关。在这里，我们通过消融 St8sia2、St8sia4 或两者，显示出具有部分或完全丧失多醣合成能力的小鼠内侧前额叶皮层（mPFC）中的中间神经元密度降低。所有 polyST 缺陷系的 mPFC 中，PV 和周细胞网络阳性细胞以及生长抑素阳性细胞减少，而 calretinin 阳性细胞和 calbindin 阳性细胞的 PV 阴性部分不受影响。在分析 polyST 缺陷型 GAD67-GFP 敲入小鼠时，证实了中间神经元数量减少。在 polyST 缺陷型胚胎中观察到神经节隆起中的前体积累和放射状迁移中间神经元数量减少。在器官型切片培养物中用内切唾液酸酶处理去除多醣会导致从神经节隆起进入大脑皮层的 GAD67-GFP 阳性中间神经元数量减少。此外，多醣的急性缺失导致中间神经元速度和主导过程长度显著降低。因此，多醣化的衰减会干扰皮质中间神经元的发育迁移，并导致特定中间神经元亚型的病理变化。这为 polyST 基因中的遗传变异、神经发育改变和神经精神疾病中的中间神经元功能障碍之间提供了可能的联系。
