A crucial role for polysialic acid in developmental interneuron migration and the establishment of interneuron densities in the mouse prefrontal cortex
A crucial role for polysialic acid in developmental interneuron migration and the establishment of interneuron densities in the mouse prefrontal cortex
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DOI：
10.1242/dev.111773
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发表时间：
2014-08-01
期刊：
影响因子：
4.6
通讯作者：
Hildebrandt, Herbert
中科院分区：
文献类型：
--
作者：
Kroecher, Tim;Roeckle, Iris;Hildebrandt, Herbert
聚唾液酸（polySia）是神经细胞粘附分子NCAM的独特聚糖修饰，是大脑发育的主要决定因素。NCAM的多唾液酰化是由两种多唾液酰转移酶（polySTs） ST8SIA2和ST8SIA4实现的。polySia-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。本研究显示，通过切除St8sia2、St8sia4或两者同时切除，部分或完全丧失polySia合成能力的小鼠，内侧前额叶皮层（mPFC）的中间神经元密度降低。在所有多st缺陷系的mPFC中，小白蛋白和神经元周围网阳性细胞以及生长抑素阳性细胞减少，而calretinin阳性细胞和calbinin阳性细胞的小白蛋白阴性部分不受影响。通过分析poly - st缺陷GAD67-GFP敲入小鼠，证实了中间神经元数量减少。在多st缺陷胚胎中观察到神经节突起中前体的积累和白质中切向迁移的中间神经元数量的减少。通过内醛苷酶处理器官型切片培养物去除多晶硅导致gad67 - gfp阳性中间神经元从神经节突起进入大脑皮层的减少。此外，polySia的急性丧失导致神经元间速度和前导过程长度显著减少。因此，polySia的衰减干扰了皮层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改变。这为神经精神疾病中多st基因的遗传变异、神经发育改变和中间神经元功能障碍提供了可能的联系。
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.