Thalamocortical Pathfinding Defects Precede Degeneration of the Reticular Thalamic Nucleus in Polysialic Acid-Deficient Mice
Thalamocortical Pathfinding Defects Precede Degeneration of the Reticular Thalamic Nucleus in Polysialic Acid-Deficient Mice
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DOI：
10.1523/jneurosci.5609-10.2011
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发表时间：
2011-01-26
影响因子：
5.3
通讯作者：
Hildebrandt, Herbert
中科院分区：
文献类型：
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作者：
Schiff, Miriam;Roeckle, Iris;Hildebrandt, Herbert
聚唾液酸 (polySia) 对神经细胞粘附分子 (NCAM) 的修饰与神经发育密切相关。 PolySia 合成酶 ST8SiaII 和 ST8SiaIV 的基因消融产生了 PolySia 阴性但 NCAM 阳性 (II-/-IV-/-) 小鼠，其特征是主要脑轴突束的严重缺陷，包括内囊发育不全。在这里，我们证明丘脑皮质纤维的误导和皮质丘脑连接的缺陷导致 II-/-IV-/- 小鼠的内囊缺陷。丘脑皮质纤维在胚胎第 14.5 天穿过网状丘脑核 (Rt) 的原基，然后未能转变为腹侧端脑，从而偏离其正常轨迹而不穿过内囊。在出生后第 1 天，观察到穿过 Rt 的纤维减少和大量瓦解，而末端脱氧核苷酸转移酶 dUTP 缺口末端标记和裂解 caspase-3 染色表明，在出生后第 5 天，Rt 神经元发生大量凋亡细胞死亡。此外，在出生后发育过程中，4 周龄 II-/-IV-/- 小鼠中的 Rt 神经元数量急剧减少，但在NCAM 缺陷的 N-/- 或 II-/-IV-/-N-/- 三重敲除动物未表现出内囊缺陷。因此，II-/-IV-/- 小鼠中 Rt 的退化可能是丘脑皮质和皮质丘脑纤维畸形的结果，这些纤维为 Rt 提供主要的兴奋性输入。事实上，在全脑切片培养物上损伤皮质丘脑纤维可以诱导 Rt 神经元的凋亡。因此，我们提出多唾液酸化缺陷、NCAM 阳性小鼠中 Rt 的顺行跨神经元变性是由丘脑皮质寻路缺陷导致的传入神经支配缺陷引起的。
The modification of the neural cell adhesion molecule (NCAM) with polysialic acid (polySia) is tightly linked to neural development. Genetic ablation of the polySia-synthesizing enzymes ST8SiaII and ST8SiaIV generates polySia-negative but NCAM-positive (II-/-IV-/-) mice characterized by severe defects of major brain axon tracts, including internal capsule hypoplasia. Here, we demonstrate that misguidance of thalamocortical fibers and deficiencies of corticothalamic connections contribute to internal capsule defects in II-/-IV-/- mice. Thalamocortical fibers cross the primordium of the reticular thalamic nucleus (Rt) at embryonic day 14.5, before they fail to turn into the ventral telencephalon, thus deviating from their normal trajectory without passing through the internal capsule. At postnatal day 1, a reduction and massive disorganization of fibers traversing the Rt was observed, whereas terminal deoxynucleotidyl transferase dUTP nick end labeling and cleaved caspase-3 staining indicated abundant apoptotic cell death of Rt neurons at postnatal day 5. Furthermore, during postnatal development, the number of Rt neurons was drastically reduced in 4-week-old II-/-IV-/- mice, but not in the NCAM-deficient N-/- or II-/-IV-/-N-/- triple knock-out animals displaying no internal capsule defects. Thus, degeneration of the Rt in II-/-IV-/- mice may be a consequence of malformation of thalamocortical and corticothalamic fibers providing major excitatory input into the Rt. Indeed, apoptotic death of Rt neurons could be induced by lesioning corticothalamic fibers on whole-brain slice cultures. We therefore propose that anterograde transneuronal degeneration of the Rt in polysialylation-deficient, NCAM-positive mice is caused by defective afferent innervation attributable to thalamocortical pathfinding defects.