Identification of multiple genetic loci linked to the propensity for "behavioral despair" in mice
Identification of multiple genetic loci linked to the propensity for "behavioral despair" in mice
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DOI：
10.1101/gr.222602
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发表时间：
2002-03-01
期刊：
影响因子：
7
通讯作者：
Nakatani, N
中科院分区：
文献类型：
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作者：
Yoshikawa, T;Watanabe, A;Nakatani, N
强迫游泳试验（FST）和悬尾试验（TST）是广泛使用的抗抑郁药筛选方法。已知多种抗抑郁药可减少FST和TST的不动时间。为了确定两种试验中不动持续时间的遗传决定因素，我们分析了来自C57 BL/6（136）和C3 H/He（0）品系间杂交的560只F2小鼠。复合区间映射揭示了五个主要位点（暗示和显着的连锁）影响不动的FST，和四个位点的TST。第8号和第11号染色体上的9个数量性状位点（QTL）在两种行为测量之间重叠。全基因组相互作用分析，这是为了确定基因座对，可能有助于上位表型，检测到两对染色体位点的TST。第11号染色体上的QTL及其相关的上位性TST-QTL在X染色体上编码γ-氨基丁酸A型（GABA）受体亚基作为候选者。对来自两个亲本品系的这些基因的序列和表达分析显示，与C3小鼠相比，136只小鼠的额叶皮层中α 1亚基基因的表达显著降低。目前的数量性状研究应该为确定抗抑郁药的新分子靶点和解开抑郁症和焦虑症的复杂遗传机制开辟道路。
The forced swim test (FST) and tail suspension test (TST) are widely used and well established screening paradigms for antidepressants. A variety of antidepressive agents are known to reduce immobility time in both FST and TST. To identify genetic determinants of immobility duration in both tests, we analyzed 560 F2 mice from an intercross between C57BL/6 (136) and C3H/He (0) strains. Composite interval mapping revealed five major loci (suggestive and significant linkage) affecting immobility in the FST, and four loci for the TST. The 9, quantitative trait loci (QTL) on chromosomes 8 and 11 overlap between the two behavioral measures. Genome-wide interaction analysis, which was developed to identify locus pairs that may contribute epistatically to a phenotype, detected two pairs of chromosomal loci for the TST. The QTL on chromosome 11 and its associated epistatic TST-QTL on chromosome X encode gamma-aminobutyric acid type A (GABA,) receptor subunits as candidates. Sequence and, expression analyses of these genes from the two parental strains revealed a significantly lower expression of the alpha1 subunit gene in the frontal cortex of 136 mice compared to C3 mice. The present quantitative trait study should open up avenues for identifying novel molecular targets for antidepressants and unraveling the complex genetic mechanisms of depressive and anxiety disorders.