Fiorelli Roberto, Rudolph Uwe, Straub Carolin J, Feldon Joram, Yee Benjamin K
Laboratory of Behavioural Neurobiology, ETH Zurich, Schorenstrasse, Schwerzenbach, Switzerland.
Behav Pharmacol. 2008 Sep;19(5-6):582-96. doi: 10.1097/FBP.0b013e32830dc0c7.
Gamma-aminobutyric acid (GABA)A receptors characterized by the presence of the alpha3 subunit are the major GABAA receptor subtype expressed in brain stem monoaminergic nuclei. These alpha3-GABAA receptors are therefore in a unique position to regulate monoaminergic functions. To characterize the functional properties of alpha3-GABAA receptors, we present a preliminary assessment of the expression of affective and cognitive behaviour in male mice with a targeted deletion of the Gabra3 gene encoding the alpha3 subunit [alpha3 knockout (KO) mice] on a C57BL/6Jx129X1/SvJ F1 hybrid genetic background. The alpha3 KO mice did not exhibit any gross change of anxiety-like behaviour or spontaneous locomotor behaviour. In the Porsolt forced swim test for potential antidepressant activity, alpha3 KO mice exhibited reduced floating and enhanced swimming behaviour relative to wild-type controls. Performance on a two-choice sucrose preference test, however, revealed no evidence for an increase in sucrose preference in the alpha3 KO mice that would have substantiated a potential phenotype for depression-related behaviour. In contrast, a suggestion of an enhanced negative contrast effect was revealed in a one-bottle sucrose consumption test across different sucrose concentrations. These affective phenotypes were accompanied by alterations in the balance between conditioned responding to the discrete conditioned stimulus and to the context, and a suggestion of faster extinction, in the Pavlovian conditioned freezing paradigm. Spatial learning in the water maze reference memory test, however, was largely unchanged in the alpha3 KO mice, except for a trend of preservation during reversal learning. The novel phenotypes following global deletion of the GABAA receptor alpha3 subunit identified here provided relevant insights, in addition to our earlier study, into the potential behavioural relevance of this specific receptor subtypes in the modulation of both affective and cognitive functions.
以α3亚基的存在为特征的γ-氨基丁酸（GABA）A受体是在脑干单胺能核中表达的主要GABAA受体亚型。因此，这些α3-GABAA受体处于调节单胺能功能的独特位置。为了表征α3-GABAA受体的功能特性，我们对在C57BL/6Jx129X1/SvJ F1杂交遗传背景下靶向缺失编码α3亚基的Gabra3基因的雄性小鼠[α3基因敲除（KO）小鼠]的情感和认知行为表达进行了初步评估。α3基因敲除小鼠未表现出焦虑样行为或自发运动行为的任何明显变化。在用于潜在抗抑郁活性的波索尔特强迫游泳试验中，与野生型对照相比，α3基因敲除小鼠表现出漂浮减少和游泳行为增强。然而，在双选蔗糖偏好试验中的表现显示，没有证据表明α3基因敲除小鼠的蔗糖偏好增加，而这本来可以证实与抑郁相关行为的潜在表型。相比之下，在不同蔗糖浓度的单瓶蔗糖消耗试验中发现了负性对比效应增强的迹象。这些情感表型伴随着在巴甫洛夫条件性冻结范式中对离散条件刺激和背景的条件反应之间平衡的改变，以及更快消退的迹象。然而，在水迷宫参考记忆试验中的空间学习在α3基因敲除小鼠中基本没有变化，除了在逆向学习过程中有保持的趋势。除了我们早期的研究之外，这里确定的GABAA受体α3亚基整体缺失后的新表型为该特定受体亚型在调节情感和认知功能方面的潜在行为相关性提供了相关见解。
