Altered neurotransmission in the mesolimbic reward system of Girk-/- mice
Altered neurotransmission in the mesolimbic reward system of Girk-/- mice
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DOI：
10.1111/j.1471-4159.2010.06864.x
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发表时间：
2010-09-01
影响因子：
4.7
通讯作者：
Wickman, Kevin
中科院分区：
文献类型：
--
作者：
Arora, Devinder;Haluk, Desirae M.;Wickman, Kevin
缺乏G蛋白门控内向整流K+通道（Girk）的Girk 2亚基的小鼠表现出多巴胺依赖性活动过度和对刺激多巴胺神经传递的药物的反应升高。在Girk 2-/-小鼠中观察到的多巴胺依赖性表型可以反映中脑多巴胺神经元的内在兴奋性增加或抑制性反馈减少，或由Girk 2消融引发的继发性适应。我们解决了这些可能性，通过评估Girk-/-小鼠的行为，电生理和细胞生物学检测集中在中脑边缘多巴胺系统。尽管Girk 1和Girk 2亚基对中脑多巴胺神经元中Girk信号传导的贡献存在差异，但Girk 1-/-和Girk 2-/-小鼠表现出相当的基线活动过度和对可卡因的反应增强。Girk消融也与腹侧被盖区多巴胺神经元传入输入的改变相关。来自Girk 1-/-和Girk 2-/-小鼠的多巴胺神经元表现出升高的多巴胺能神经传递，这与α-氨基-3-羟基-5-甲基-4-异恶唑丙酸盐谷氨酸受体的突触水平增加有关。此外，突触密度，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯受体水平，和多巴胺能神经传递升高，在中等多刺神经元的神经核的Girk 1-/-和Girk 2-/-小鼠。我们的结论是，多巴胺依赖的表型在Girk 2-/-小鼠并不完全归因于损失的Girk信号在多巴胺神经元，并可能涉及次级适应促进mesolimbic奖励系统中的神经元信号。
P>Mice lacking the Girk2 subunit of G protein-gated inwardly rectifying K+ (Girk) channels exhibit dopamine-dependent hyperactivity and elevated responses to drugs that stimulate dopamine neurotransmission. The dopamine-dependent phenotypes seen in Girk2-/- mice could reflect increased intrinsic excitability of or diminished inhibitory feedback to midbrain dopamine neurons, or secondary adaptations triggered by Girk2 ablation. We addressed these possibilities by evaluating Girk-/- mice in behavioral, electrophysiological, and cell biological assays centered on the mesolimbic dopamine system. Despite differences in the contribution of Girk1 and Girk2 subunits to Girk signaling in midbrain dopamine neurons, Girk1-/- and Girk2-/- mice exhibited comparable baseline hyperactivities and enhanced responses to cocaine. Girk ablation also correlated with altered afferent input to dopamine neurons in the ventral tegmental area. Dopamine neurons from Girk1-/- and Girk2-/- mice exhibited elevated glutamatergic neurotransmission, paralleled by increased synaptic levels of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptors. In addition, synapse density, alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor levels, and glutamatergic neurotransmission were elevated in medium spiny neurons of the nucleus accumbens from Girk1-/- and Girk2-/- mice. We conclude that dopamine-dependent phenotypes in Girk2-/- mice are not solely attributable to a loss of Girk signaling in dopamine neurons, and likely involve secondary adaptations facilitating glutamatergic signaling in the mesolimbic reward system.