Belichenko Pavel V, Kleschevnikov Alexander M, Salehi Ahmad, Epstein Charles J, Mobley William C
Department of Neurology & Neurological Sciences and the Center for Research and Treatment of Down Syndrome, Stanford University Medical Center, Stanford, California 94305-5489, USA.
J Comp Neurol. 2007 Oct 1;504(4):329-45. doi: 10.1002/cne.21433.
Down syndrome (DS) is caused by trisomy of human chromosome 21. Because Ts65Dn and Ts1Cje mice are segmentally trisomic for a region of mouse chromosome 16, they genetically model DS and are used to study pathogenic mechanisms. Previously, we provided evidence for changes in both the structure and function of pre- and postsynaptic elements in the Ts65Dn mouse. Striking changes were evident in the size of the dendritic spines and in the ability to induce long-term potentiation (LTP) in the fascia dentata (FD). To explore the genetic basis for these changes, we examined Ts1Cje mice, which are trisomic for a completely overlapping but smaller segment of mouse chromosome 16. As in the Ts65Dn mouse, there was a regionally selective decrease in the density of dendritic spines ( approximately 12%), an increase in the size of spine heads ( approximately 26%), a decrease in the length of spine necks ( approximately 26%), and reorganization of inhibitory inputs with a relative decrease in inputs to dendrite shafts and spine heads and a significant increase to the necks of spines (6.4%). Thus, all of the Ts65Dn phenotypes were present, but they were significantly less severe. In contrast, and just as was the case for the Ts65Dn mouse, LTP could not be induced unless the selective gamma-aminobutyric acid (GABA)(A) receptor antagonist picrotoxin was applied. Therefore, there was conservation of important synaptic phenotypes in the Ts1Cje mice. The analysis of data from this and earlier studies points to genotype-phenotype linkages in DS whose complexity ranges from relatively simple to quite complex.
唐氏综合征（DS）由人类21号染色体三体性引起。由于Ts65Dn和Ts1Cje小鼠在小鼠16号染色体的一个区域存在节段性三体，它们可作为DS的遗传模型，用于研究致病机制。此前，我们已提供证据表明Ts65Dn小鼠突触前和突触后元件的结构和功能均发生了变化。齿状回（FD）中树突棘的大小以及诱导长时程增强（LTP）的能力出现了显著变化。为探究这些变化的遗传基础，我们检测了Ts1Cje小鼠，其在小鼠16号染色体一个完全重叠但较小的节段存在三体。与Ts65Dn小鼠一样，树突棘密度存在区域选择性降低（约12%），棘头大小增加（约26%），棘颈长度缩短（约26%），抑制性输入发生重组，向树突干和棘头的输入相对减少，而向棘颈的输入显著增加（6.4%）。因此，Ts65Dn小鼠的所有表型均存在，但严重程度明显较低。相比之下，正如Ts65Dn小鼠的情况一样，除非应用选择性γ-氨基丁酸（GABA）（A）受体拮抗剂印防己毒素，否则无法诱导LTP。因此，Ts1Cje小鼠中存在重要的突触表型保守性。对本研究及早期研究数据的分析表明，DS中存在基因型-表型联系，其复杂性范围从相对简单到相当复杂。
