Roles of kainate receptors in behavioral plasticity rela

红藻氨酸受体在行为可塑性关系中的作用

• 批准号: 7312942
• 负责人: HUSSEINI K MANJI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7312942
• 关键词: Roles; kainate; receptors; behavioral; plasticity

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.

红藻氨酸受体 (KAR) 调节谷氨酸和 GABA 的释放以及参与情绪调节的不同大脑区域的突触可塑性，包括前扣带皮层、海马体和杏仁核。 KAR 家族包括五个亚基：GluR5-7 和 KA-1-2（分别也称为谷氨酸受体离子型红藻氨酸 (GRIK) 1-5）。受体形成异源三聚体或同源三聚体（仅限 GluR5-7）。 GluR5 和 6 可以进行 RNA 编辑，从而改变通道对不同离子的通透性。不同 KAR 亚基的细胞表面表达受到受体转录物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，多项双相情感障碍连锁研究已暗示该区域。最近的遗传关联研究直接表明 GluR6 是情绪障碍风险增加的一个促成因素。然而，红藻氨酸受体在情绪调节中的作用很大程度上未知。因此，我们使用行为测试电池对 GluR5 和 GluR6 敲除 (KO) 小鼠和野生型对照小鼠进行了情绪障碍和神经化学实验的研究。 GluR5 和 6 KO 小鼠似乎获得了正常生长，并且没有神经系统异常。与 WT 和 GluR5 KO 小鼠相比，GluR6 KO 小鼠消耗更多的糖精甜味剂溶液，这是享乐活动的指标。 GluR6 KO 行进了更长的距离，进入并在开放场地的中心停留了更多的时间（这可以作为一般活动以及探索性冒险活动的指标）。 GluR6 KO 的过度活跃在整个实验期间持续存在，并且它们没有表现出对开放场地的习惯。 GluR6 KO 在社交互动和居民入侵者测试中都表现出攻击性。 GluR6 KO 在高架十字迷宫的开臂中具有更多的活性，并且在强迫游泳测试中具有更少的不动性。 GluR6 KO 在苯丙胺激发试验中也表现出更高的反应。总之，GluR6（而非 GluR5）KO 小鼠在整个实验过程中表现出行为兴奋、更强的攻击性和快感亢进；这些似乎是临床躁狂状态的表型。此外，长期锂治疗缓解了 GluR6 KO 小鼠的关键行为改变，包括运动活动增强、攻击性加剧和对安非他明超敏感。因此，数据强烈支持这样的观点：GluR6 神经传递是情绪相关行为的关键调节剂，并且 GluR6 神经传递的遗传功能障碍可能导致躁狂样行为的行为表现。未来的研究需要阐明人类 GluR6 SNP 对 GluR6 功能和相关神经传递、参与 GluR6 药物情绪样行为可塑性的大脑区域以及 GluR6 作为开发情绪影响剂的新靶点的影响。