Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal
Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal
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DOI：
10.1172/jci61319
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发表时间：
2012-06-01
影响因子：
15.9
通讯作者：
Palmer, Abraham A.
中科院分区：
文献类型：
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作者：
Distler, Margaret G.;Plant, Leigh D.;Palmer, Abraham A.
Glycoproteinase 1（Glo 1）的表达以前曾与小鼠的焦虑有关;然而，它在焦虑中的作用是有争议的，其潜在的机制是未知的。在这里，我们证明GLO 1通过降低GABA（A）受体激动剂甲基乙二醛（MG）的水平来增加焦虑。在Tg细菌人工染色体上过表达Glo 1的小鼠表现出焦虑样行为增加和脑MG浓度降低。低剂量MG治疗可减少焦虑样行为，而高剂量MG可引起运动抑制、共济失调和体温过低，这些是GABA（A）受体激活的特征性效应。与这些数据一致，我们发现生理浓度的MG选择性激活初级神经元中的GABA（A）受体。这些数据表明，GLO 1通过降低MG水平增加焦虑，从而降低GABA（A）受体活化。更广泛地说，我们的研究结果可能将代谢状态，神经元抑制音和行为联系起来。最后，我们证明，药物抑制GLO 1减少焦虑，这表明GLO 1是一个可能的目标，用于治疗焦虑症。
Glyoxalase 1 (Glo1) expression has previously been associated with anxiety in mice; however, its role in anxiety is controversial, and the underlying mechanism is unknown. Here, we demonstrate that GLO1 increases anxiety by reducing levels of methylglyoxal (MG), a GABA(A) receptor agonist. Mice overexpressing Glo1 on a Tg bacterial artificial chromosome displayed increased anxiety-like behavior and reduced brain MG concentrations. Treatment with low doses of MG reduced anxiety-like behavior, while higher doses caused locomotor depression, ataxia, and hypothermia, which are characteristic effects of GABA(A) receptor activation. Consistent with these data, we found that physiological concentrations of MG selectively activated GABA(A) receptors in primary neurons. These data indicate that GLO1 increases anxiety by reducing levels of MG, thereby decreasing GABA(A) receptor activation. More broadly, our findings potentially link metabolic state, neuronal inhibitory tone, and behavior. Finally, we demonstrated that pharmacological inhibition of GLO1 reduced anxiety, suggesting that GLO1 is a possible target for the treatment of anxiety disorders.