Developmental delay in motor skill acquisition in Niemann-Pick C1 mice reveals abnormal cerebellar morphogenesis.
Developmental delay in motor skill acquisition in Niemann-Pick C1 mice reveals abnormal cerebellar morphogenesis.
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DOI：
10.1186/s40478-016-0370-z
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发表时间：
2016-09-01
影响因子：
7.1
通讯作者：
Fiorenza MT
中科院分区：
文献类型：
--
作者：
Caporali P;Bruno F;Palladino G;Dragotto J;Petrosini L;Mangia F;Erickson RP;Canterini S;Fiorenza MT
尼曼-皮克C1型（NPC 1）病是一种由外源性胆固醇细胞内运输缺陷引起的溶酶体储存障碍。浦肯野细胞（PC）变性是NPC 1患者和动物模型中小脑功能障碍的主要标志。最近的研究表明，Sonic hedgehog（Shh）表达的显著减少降低了Npc 1 −/−小鼠小脑发育中颗粒神经元前体的增殖潜力。追求这一发展缺陷转化为功能障碍的假设，我们已经测定了属于轻度突变小鼠品系Npc 1 nmf 164的Npc 1缺陷幼崽的感觉运动发育从出生后第3天（PN）到PN 21。Npc 1 nmf 164/Npc 1 nmf 164幼仔表现出2.5天的延迟收购复杂的运动能力相比，野生型（wt）同窝仔，在协议之间观察到的PN 11和PN 15小脑皮质细胞结构的显着紊乱。与野生型相比，Npc 1 nmf 164纯合子小鼠表现出较差的形态分化的Bergmann胶质细胞（BG），所示的较厚的径向轴和不太精细的网状图案的侧突。BG功能发育也有缺陷，如GLAST和谷氨酰胺合成酶表达的显著降低所示。VGluT 2和GAD 65表达的减少也表明PC分别通过攀爬/平行纤维和篮状/星状细胞接受的谷氨酸能/GABA能刺激的整体紊乱。最后，Npc 1缺陷也影响了少突胶质细胞的分化，如髓磷脂碱性蛋白的强烈减少所示。在PN 4和PN 7连续两次给予2-羟丙基-β-环糊精抵消了这些缺陷，部分预防了BG的功能损害，并完全恢复了对PC的谷氨酸能/GABA能刺激的正常模式。这些研究结果表明，在Npc 1 nmf 164纯合子小鼠在小脑形态发生过程中的突触连接和髓鞘形成障碍的紊乱在很大程度上预测运动缺陷，通常在成年期观察到。本文的在线版本（doi：10.1186/s40478-016-0370-z）包含补充材料，可供授权用户使用。
Niemann-Pick type C1 (NPC1) disease is a lysosomal storage disorder caused by defective intracellular trafficking of exogenous cholesterol. Purkinje cell (PC) degeneration is the main sign of cerebellar dysfunction in both NPC1 patients and animal models. It has been recently shown that a significant decrease in Sonic hedgehog (Shh) expression reduces the proliferative potential of granule neuron precursors in the developing cerebellum of Npc1−/− mice. Pursuing the hypothesis that this developmental defect translates into functional impairments, we have assayed Npc1-deficient pups belonging to the milder mutant mouse strain Npc1nmf164 for sensorimotor development from postnatal day (PN) 3 to PN21. Npc1nmf164/ Npc1nmf164 pups displayed a 2.5-day delay in the acquisition of complex motor abilities compared to wild-type (wt) littermates, in agreement with the significant disorganization of cerebellar cortex cytoarchitecture observed between PN11 and PN15. Compared to wt, Npc1nmf164 homozygous mice exhibited a poorer morphological differentiation of Bergmann glia (BG), as indicated by thicker radial shafts and less elaborate reticular pattern of lateral processes. Also BG functional development was defective, as indicated by the significant reduction in GLAST and Glutamine synthetase expression. A reduced VGluT2 and GAD65 expression also indicated an overall derangement of the glutamatergic/GABAergic stimulation that PCs receive by climbing/parallel fibers and basket/stellate cells, respectively. Lastly, Npc1-deficiency also affected oligodendrocyte differentiation as indicated by the strong reduction of myelin basic protein. Two sequential 2-hydroxypropyl-β-cyclodextrin administrations at PN4 and PN7 counteract these defects, partially preventing functional impairment of BG and fully restoring the normal patterns of glutamatergic/GABAergic stimulation to PCs. These findings indicate that in Npc1nmf164 homozygous mice the derangement of synaptic connectivity and dysmyelination during cerebellar morphogenesis largely anticipate motor deficits that are typically observed during adulthood. The online version of this article (doi:10.1186/s40478-016-0370-z) contains supplementary material, which is available to authorized users.
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影响因子：
2.7
作者：
Cameron, D. Bryant;Kasai, Kazue;Jiang, Yulan;Hu, Taofang;Saeki, Yoshinaga;Komuro, Hitoshi
通讯作者：
Komuro, Hitoshi
影响因子：
4.6
作者：
Corrales, JMD;Rocco, GL;Joyner, AL
通讯作者：
Joyner, AL
DOI：
10.1523/jneurosci.1317-11.2011
发表时间：
2011-06-22
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Aqul A;Liu B;Ramirez CM;Pieper AA;Estill SJ;Burns DK;Liu B;Repa JJ;Turley SD;Dietschy JM
通讯作者：
Dietschy JM
影响因子：
3.7
作者：
Davidson CD;Ali NF;Micsenyi MC;Stephney G;Renault S;Dobrenis K;Ory DS;Vanier MT;Walkley SU
通讯作者：
Walkley SU
影响因子：
3.5
作者：
Grimes, JM;Ricci, LA;Melloni, RH
通讯作者：
Melloni, RH