Hill Joanna M, Ades Anne M, McCune Susan K, Sahir Nadia, Moody Elizabeth M, Abebe Daniel T, Crnic Linda S, Brenneman Douglas E
Section on Developmental and Molecular Pharmacology, NICHD, NIH, Bethesda, MD 20892, USA.
Exp Neurol. 2003 Sep;183(1):56-65. doi: 10.1016/s0014-4886(03)00164-x.
The most common genetic cause of mental retardation is Down syndrome, trisomy of chromosome 21, which is accompanied by small stature, developmental delays, and mental retardation. In the Ts65Dn segmental trisomy mouse model of Down syndrome, the section of mouse chromosome 16 most homologous to human chromosome 21 is trisomic. This model exhibits aspects of Down syndrome including growth restriction, delay in achieving developmental milestones, and cognitive dysfunction. Recent data link vasoactive intestinal peptide malfunction with developmental delays and cognitive deficits. Blockage of vasoactive intestinal peptide during rodent development results in growth and developmental delays, neuronal dystrophy, and, in adults, cognitive dysfunction. Also, vasoactive intestinal peptide is elevated in the blood of newborn children with autism and Down syndrome. In the current experiments, vasoactive intestinal peptide binding sites were significantly increased in several brain areas of the segmental trisomy mouse, including the olfactory bulb, hippocampus, cortex, caudate/putamen, and cerebellum, compared with wild-type littermates. In situ hybridization for VIP mRNA revealed significantly more dense vasoactive intestinal peptide mRNA in the hippocampus, cortex, raphe nuclei, and vestibular nuclei in the segmental trisomy mouse compared with wild-type littermates. In the segmental trisomy mouse cortex and hippocampus, over three times as many vasoactive intestinal peptide-immunopositive cells were visible than in wild-type mouse cortex. These abnormalities in vasoactive intestinal peptide parameters in the segmental trisomy model of Down syndrome suggest that vasoactive intestinal peptide may have a role in the neuropathology of Down-like cognitive dysfunction.
智力发育迟缓最常见的遗传原因是唐氏综合征，即21号染色体三体，常伴有身材矮小、发育迟缓以及智力发育迟缓。在唐氏综合征的Ts65Dn节段性三体小鼠模型中，小鼠16号染色体上与人类21号染色体最同源的部分出现三体。该模型表现出唐氏综合征的一些特征，包括生长受限、发育里程碑延迟以及认知功能障碍。最近的数据表明血管活性肠肽功能异常与发育迟缓及认知缺陷有关。在啮齿动物发育过程中阻断血管活性肠肽会导致生长和发育延迟、神经元营养不良，在成年动物中还会导致认知功能障碍。此外，患有自闭症和唐氏综合征的新生儿血液中血管活性肠肽水平升高。在当前实验中，与野生型同窝小鼠相比，节段性三体小鼠的几个脑区，包括嗅球、海马体、皮质、尾状核/壳核和小脑，血管活性肠肽结合位点显著增加。血管活性肠肽mRNA的原位杂交显示，与野生型同窝小鼠相比，节段性三体小鼠海马体、皮质、中缝核和前庭核中血管活性肠肽mRNA的密度明显更高。在节段性三体小鼠的皮质和海马体中，可见的血管活性肠肽免疫阳性细胞数量是野生型小鼠皮质中的三倍多。唐氏综合征节段性三体模型中血管活性肠肽参数的这些异常表明，血管活性肠肽可能在类似唐氏综合征的认知功能障碍的神经病理学中起作用。
