Behavioral Characterization of Knockin Mice with Mutations M287L and Q266I in the Glycine Receptor α1 Subunit
Behavioral Characterization of Knockin Mice with Mutations M287L and Q266I in the Glycine Receptor α1 Subunit
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DOI：
10.1124/jpet.111.185124
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发表时间：
2012-02-01
影响因子：
3.5
通讯作者：
Harris, R. Adron
中科院分区：
文献类型：
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作者：
Blednov, Yuri A.;Benavidez, Jill M.;Harris, R. Adron
我们使用行为药理学来表征甘氨酸受体 (GlyR) α 1 亚基突变（Q266I 或 M287L）的杂合敲入小鼠 (J Pharmacol Exp Ther 340: 304-316, 2012)。这些突变旨在减少 (M287L) 或消除 (Q266I) 乙醇对 GlyR 功能的增强作用。我们询问 Q266I 突变体中乙醇的哪些行为影响会比 M287L 减少更多，并发现旋转共济失调是满足这一标准的行为。与对照组相比，突变小鼠在乙醇消耗、乙醇刺激的惊恐反应、急性身体依赖性迹象以及乙醇、丁醇、氯胺酮、戊巴比妥和氟西泮产生的翻正反应丧失持续时间方面也存在差异。通过急性注射低剂量、亚惊厥剂量的士的宁，在野生型小鼠中模仿了其中一些行为变化。两种突变体都表现出增加的听觉惊吓反应和对士的宁癫痫发作的敏感性增加。因此，除了减少乙醇对 GlyR 的作用外，这些突变还减少了甘氨酸能抑制，这也可能改变对 GABA 能药物的敏感性。
We used behavioral pharmacology to characterize heterozygous knockin mice with mutations (Q266I or M287L) in the alpha 1 subunit of the glycine receptor (GlyR) (J Pharmacol Exp Ther 340: 304-316, 2012). These mutations were designed to reduce (M287L) or eliminate (Q266I) ethanol potentiation of GlyR function. We asked which behavioral effects of ethanol would be reduced more in the Q266I mutant than the M287L and found rotarod ataxia to be the behavior that fulfilled this criterion. Compared with controls, the mutant mice also differed in ethanol consumption, ethanol-stimulated startle response, signs of acute physical dependence, and duration of loss of righting response produced by ethanol, butanol, ketamine, pentobarbital, and flurazepam. Some of these behavioral changes were mimicked in wild-type mice by acute injections of low, subconvulsive doses of strychnine. Both mutants showed increased acoustic startle response and increased sensitivity to strychnine seizures. Thus, in addition to reducing ethanol action on the GlyRs, these mutations reduced glycinergic inhibition, which may also alter sensitivity to GABAergic drugs.