Identification and functional analysis of genes for learning and memory dysfunction by using Senescence Accelerating Mouse

1)将年龄相关学习记忆功能障碍的衰老加速小鼠（Senescence Accelerated Mouse, SAMP8） P8品系与表型正常的日本野生小鼠衍生的JF1品系进行配对，获得F2小鼠。我们利用120多个遗传标记对5月龄的F2小鼠进行了全基因组QTL分析，在1、13和15号染色体上发现了4个显著的QTL位点。有趣的是，虽然1号和13号染色体上的候选位点来自SAMP8背景，但15号染色体上的两个位点来自JF1背景，尽管它被用作正常对照。2)通过与JF1菌株回交，在JF1背景下建立了3株携带SAMP8衍生染色体1、13和15的速度基因菌株。3)通过对每个候选区域的详尽分析，我们发现1号和13号染色体上分别有3个和1个基因携带多态性，其氨基酸替换分别是SAM菌株特有的。在JF1菌株15号染色体的2个位点上，分别发现7个和2个基因携带与氨基酸替换相关的多态性。4)在SAM菌株13号染色体上发现了一个离子通道编码基因的特异性多态性。当该基因在培养细胞中表达时，我们发现其离子通透性与正常对照相比存在差异。这一差异表明离子通道参与了学习和记忆功能障碍，尽管还需要进一步的表征。

1) We have obtained F2 mice by mating P8 strain of Senescence Accelerated Mouse (SAMP8) exhibiting age related learning and memory dysfunction with Japanese wild mouse derived JF1 strain showing normal phenotype. We have performed genome-wide QTL analysis on these F2 mice at the age of 5 month by Step Through experiment with more than 120 genetic markers, and found four significant QTL loci on chromosomes 1, 13 and 15. Interestingly, while the candidate loci on Chromosomes 1 and 13 were derived from SAMP8 background, two loci on chromosome 15 were found to be from JF1 background despite it was used as normal control.2) Three speed-congenic strains carrying either SAMP8 derived chromosomes 1, 13, or 15 in JF1 background were established by backcrossing F1 strain with JF1 strain.3) By exhaustive analysis of each candidate regions, we found 3 and 1 genes on chromosomes 1 and 13 carry polymorphisms whose amino acid replacements were specific to the SAM strain, respectively. In 2 loci on chromosome 15, we found 7 and 2 genes carrying polymorphisms associated with amino acid replacements in JF1 strain, respectively.4) The SAM strain specific polymorphism on chromosome 13 was found in a gene coding for an ion channel. When this gene was expressed in cultured cells, we found difference in ion permeability compared with normal control by patch clump methods. This difference suggests the involvement of the ion channel in learning and memory dysfunction although further characterizations are needed.