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

1)我们通过将表现出与年龄相关的学习和记忆功能障碍的衰老加速小鼠（SAMP8）的P8品系与表现出正常表型的日本野生小鼠衍生的JF1品系交配获得F2小鼠。利用120多个遗传标记对5月龄的F2代小鼠进行了全基因组QTL分析，在第1、13和15染色体上发现了4个显著的QTL位点。有趣的是，虽然染色体1和13上的候选基因座来自SAMP8背景，但发现染色体15上的两个基因座来自JF1背景，尽管它被用作正常对照。3）通过对每个候选区域的详尽分析，我们在1号和13号染色体上分别发现了3个和1个基因携带多态性，其氨基酸替换是SAM株所特有的。在15号染色体上的2个位点上，分别发现7个和2个与JF1株氨基酸置换相关的基因多态性。4）在13号染色体上的一个离子通道基因中发现SAM株特异性多态性。当该基因在培养的细胞中表达时，我们发现与正常对照相比，通过斑块方法的离子渗透性的差异。这种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.