Quantitative trait locus analysis identifies Gabra3 as a regulator of behavioral despair in mice.
Quantitative trait locus analysis identifies Gabra3 as a regulator of behavioral despair in mice.
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DOI：
10.1007/s00335-010-9266-6
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发表时间：
2010-06
期刊：
影响因子：
2.5
通讯作者：
Pletcher, Mathew T.
中科院分区：
文献类型：
--
作者：
Miller, Brooke H.;Schultz, Laura E.;Long, Bradley C.;Pletcher, Mathew T.
悬尾试验（TST），测量行为绝望，被广泛用作人类抑郁症和抗抑郁疗效的动物模型。为了鉴定参与调节TST性能的新基因，我们将在TST中表现出低不动性的近交系（RIIIS/J）与两个高不动性品系（C57 BL/6 J和NZB/BlNJ）杂交以产生两个不同的F2杂交群体。使用一组SNP标记对所有F2后代（n = 655）进行高密度基因分型。F2群体的全基因组区间作图在小鼠染色体（MMU）4、6和X上发现了统计学显著的数量性状位点（QTL）。通过对三个亲本品系海马基因表达的微阵列分析，在NZB/BlNJ × RIIIS/J杂交中鉴定的MMUX QTL内鉴定潜在的候选基因。编码GABAA受体α3亚基的Gabra 3在B6和RIIIS小鼠的海马中表达稳健，但在NZB海马组织中不存在。为了验证Gabra 3在体内调节TST行为中的作用，用SB-205384（α3亚基的正调节剂）处理小鼠。SB-205384显著降低了B6小鼠的TST不动性，而不影响一般活动，但对NZB小鼠的行为没有影响。这项工作表明，GABRA 3调节抑郁症的行为内表型，并将该基因确立为研究和治疗人类抑郁症的可行新靶点。本文的在线版本（doi：10.1007/s 00335 -010-9266-6）包含补充材料，可供授权用户使用。
The Tail Suspension Test (TST), which measures behavioral despair, is widely used as an animal model of human depressive disorders and antidepressant efficacy. In order to identify novel genes involved in the regulation of TST performance, we crossed an inbred strain exhibiting low immobility in the TST (RIIIS/J) with two high-immobility strains (C57BL/6J and NZB/BlNJ) to create two distinct F2 hybrid populations. All F2 offspring (n = 655) were genotyped at high density with a panel of SNP markers. Whole-genome interval mapping of the F2 populations identified statistically significant quantitative trait loci (QTLs) on mouse chromosomes (MMU) 4, 6, and X. Microarray analysis of hippocampal gene expression in the three parental strains was used to identify potential candidate genes within the MMUX QTLs identified in the NZB/BlNJ × RIIIS/J cross. Expression of Gabra3, which encodes the GABAA receptor α3 subunit, was robust in the hippocampus of B6 and RIIIS mice but absent from NZB hippocampal tissue. To verify the role of Gabra3 in regulating TST behavior in vivo, mice were treated with SB-205384, a positive modulator of the α3 subunit. SB-205384 significantly reduced TST immobility in B6 mice without affecting general activity, but it had no effect on behavior in NZB mice. This work suggests that GABRA3 regulates a behavioral endophenotype of depression and establishes this gene as a viable new target for the study and treatment of human depression. The online version of this article (doi:10.1007/s00335-010-9266-6) contains supplementary material, which is available to authorized users.
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DOI：
10.1073/pnas.89.15.6726
发表时间：
1992-08-01
影响因子：
11.1
作者：
FRITSCHY, JM;BENKE, D;MOHLER, H
通讯作者：
MOHLER, H
影响因子：
10.6
作者：
Liu, Xiaoqing;Stancliffe, Devin;Gershenfeld, Howard K.
通讯作者：
Gershenfeld, Howard K.
影响因子：
11
作者：
Peters, EJ;Slager, SL;Hamilton, SP
通讯作者：
Hamilton, SP
影响因子：
3.6
作者：
Crowley, JJ;Jones, MD;Lucki, I
通讯作者：
Lucki, I
影响因子：
--
作者：
Sanacora, G;Mason, GF;Krystal, JH
通讯作者：
Krystal, JH