Roles of kainate receptors in behavioral plasticity rela

海人酸受体(KARs)调节谷氨酸和GABA的释放以及参与情绪调节的不同脑区的突触可塑性，包括前扣带回皮质、海马体和杏仁核。KAR家族包括5个亚基：GluR5-7和KA-1-2(也分别称为谷氨酸受体亲离子海藻酸(GRIK)1-5)。受体形成异源三聚体或同源三聚体(仅GluR5-7)。GluR5和GluR6可以进行RNA编辑，导致通道对不同离子的通透性改变。不同KAR亚基的细胞表面表达受受体转录本的选择性剪接和受体亚型的运输特性的调节。GluR6基因位于染色体6q16.3-q21上，该区域在多个双相情感障碍连锁研究中被发现。最近的遗传关联研究直接表明GluR6是导致情绪障碍风险增加的一个因素。然而，红藻氨酸受体在情绪调节中的作用在很大程度上是未知的。因此，我们在GluR5和GluR6基因敲除(KO)小鼠和野生型对照小鼠中进行了研究，使用了情绪障碍的行为测试组件和神经化学实验。 GluR5和6KO小鼠似乎获得了正常的生长，并且没有神经异常。与WT和GluR5 KO小鼠相比，GluR6 KO小鼠消耗了更多的糖精甜味剂，这是享乐活动的一个指标。GluR6 KO走的距离更远，进入开阔场地中心的时间更长(这可以作为一般活动和探索性冒险活动的指标)。在整个实验期间，GluR6 KO的过度活动持续存在，它们没有表现出对开阔场地的适应。GluR6 KO在社会互动和居民-入侵者测试中都表现出攻击性。在强迫游泳实验中，GluR6 KO在高架迷宫的开臂活动较多，而在强迫游泳试验中较少不动。在苯丙胺激发试验中，GluR6 KO也表现出较高的反应性。综上所述，GluR6，而不是GluR5，KO小鼠在整个实验过程中表现出行为兴奋，更大的攻击性和快感；这些似乎是临床躁狂状态的表现。此外，慢性锂治疗缓解了GluR6 KO小鼠的关键行为变化，包括运动活动增加、攻击加剧和对苯丙胺超敏。因此，这些数据有力地支持了这样的观点，即GluR6神经传递是情绪相关行为的关键调节器，GluR6神经传递的遗传障碍可以导致躁狂样行为的行为表现。未来的研究还需要阐明人类GluR6 SNPs对GluR6功能和相关神经传递的影响，GluR6参与GluR6药物情绪样行为可塑性的脑区，以及GluR6作为开发情绪影响药物的新靶点。

Kainate receptors (KARs) regulate the release of glutamate and GABA and synaptic plasticity in different brain regions involved in mood regulation, including the anterior-cingulate cortex, hippocampus, and amygdala. The KAR family includes five subunits: GluR5-7 and KA-1-2 (also called glutamate receptor ionotropic kainate (GRIK) 1-5 respectively). The receptors form hetereotrimers or homotrimers (GluR5-7 only). GluR5 and 6 can undergo RNA editing, resulting in altered channel permeability to different ions. The cell surface expression of the different KAR subunits is regulated by alternative splicing of receptor transcripts and trafficking properties of the receptor subtypes. The GluR6 gene is on chromosome 6q16.3-q21, a region of which has been implied in several bipolar disorder linkage studies. Recent genetic association studies directly implicates GluR6 as a contributing factor to increased risk of mood disorders. However, the roles of kainate receptors in mood regulation are largely unknown. Therefore we conducted studies in GluR5 and GluR6 knockout (KO) and wild-type control mice using a behavioral test battery for mood disorders and neurochemical experiments. GluR5 and 6 KO mice appeared to attain normal growth, and lacked neurological abnormalities. Compared to WT and GluR5 KO mice, GluR6 KO consumed more saccharin sweeten solution, an indicator of hedonic activity. GluR6 KO traveled longer distances, entered and spent more time in the center of the open field (which can serve as indices for general activity as well as explorative-risk-taking activities). The hyperactivity of GluR6 KO persisted throughout the entire experimental period and they showed no habituation to the open-field arena. GluR6 KO exhibited aggressiveness in both the social interaction and resident-intruder tests. GluR6 KO had more activity in the open-arm of an elevated plus maze and less immobility in the forced swim test. GluR6 KO also exhibited higher responses in amphetamine challenge test. In summary, GluR6, but not GluR5, KO mice display behavioral excitement throughout experiments, greater aggressiveness, and hyperhedonia; these appear to phenocopy of the clinical manic state. Furthermore, chronic lithium treatment relieved key behavioral alterations of GluR6 KO mice including heightened locomotor activity, aggravated aggression and supersensitivity to amphetamine. Thus, the data strongly support the notion that GluR6 neurotransmission is a critical modulator of mood related behavior and that genetic dysfunction of GluR6 neurotransmission can result in behavioral display of mania-like behavior. Future studies are needed to elucidate the effects of human GluR6 SNPs on the function of GluR6 and related neurotransmission, brain regions involved in GluR6 medicated mood-like behavioral plasticity, and GluR6 as novel targets for developing mood affecting agents.