Roles of kainate receptors in behavioral plasticity related to mood disorders

红藻氨酸受体在情绪障碍相关行为可塑性中的作用

• 批准号: 7735197
• 负责人: HUSSEINI K MANJI
• 金额: $ 34.01万
• 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/7735197
• 关键词: Acceleration; Adolescent; Affect; Age; Aggressive behavior; Agitation; Alternative Splicing; Amphetamines; Amygdaloid structure; Anterior; Antidepressive Agents; Behavior; Behavioral; Behavioral Genetics; Bipolar Disorder; Boxing; Brain region; Cell surface; Child; Chromosomes; Chronic; Citalopram; Clinical; Data; Disease; Etiology; Exhibits; Family; Feeling suicidal; Functional disorder; Future; Genes; Genetic; Genotype; Glutamate Receptor; Glutamates; Goals; Growth; Hippocampus (Brain); Human; Hyperactive behavior; Impulsivity; Individual; Ions; Kainic Acid Receptors; Knock-out; Knockout Mice; Lithium; Manic; Membrane; Mood Disorders; Moods; Motor Activity; Mus; N-Methyl-D-Aspartate Receptors; Neurologic; Patients; Permeability; Pharmaceutical Preparations; Phenocopy; Population; Property; RNA Editing; Risk; Risk-Taking; Role; Saccharin; Selective Serotonin Reuptake Inhibitor; Social Interaction; Solutions; Suicide; Susceptibility Gene; Swimming; Synaptic plasticity; Testing; Therapeutic; Time; Transcript; Travel; United States Food and Drug Administration; Upper arm; Week; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; behavior test; cingulate cortex; dysphoria; gamma-Aminobutyric Acid; genetic association; hedonic; indexing; kainate; mood regulation; neurochemistry; neurotransmission; novel; prescription document; prescription procedure; receptor; research study; response; trafficking

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.<br>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. Thus, 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. Neurochemical experiments did not reveal any significant alterations of AMPA and NMDA receptors, however, hippocampal and prefrontal cortical membrane levels of GluR5 and KA-2 receptors were decreased in GluR6 KO mice, and chronic lithium treatment did not affect these decreases. Taken together, 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. Concerns that antidepressants (SSRIs) are potentially associated with suicidal thinking and/or behavior, especially in children and adolescents, led the FDA to issue a black box warning for those medications. The warning has resulted in decreased SSRI prescriptions in the young, with a concomitant increase in suicides in this population, emphasizing the need to identify the mechanisms whereby SSRIs may be associated with suicidal ideation in this population. Recent genetic studies show that the gene GRIK2 (which encodes for the GluR6 kainate receptor) confers sensitivity to treatment-emergent suicidal ideation in individuals with mood disorders. Additionally, the GRIK2 gene has been suggested to represent a bipolar susceptibility gene. Notably, antidepressants may be deleterious to bipolar disorder patients, because they may induce cycle acceleration, or cause agitation/dysphoria. Considering these and our findings with GluR6 KO mice, we hypothesized that mice (especially prepubertal mice) with altered GluR6 function would exhibit elevated levels of these behaviors as a response to SSRIs. Our preliminary data showed that aggression levels increased with age in all GluR6 genotype (WT, HET and KO) groups. Compared to GluR6 HET and WT mice, GluR6 KO mice exhibited elevated aggressive behavior. Two week citalopram treatment only increases aggression in GluR6 KO, but not WT mice. We are currently assessing the influence of citalopram on irritability and impulsivity behaviors in GluR6 KO mice.

红藻氨酸受体（KARs）调节谷氨酸和GABA的释放以及参与情绪调节的不同脑区（包括前扣带皮层、海马和杏仁核）中的突触可塑性。KAR家族包括五个亚基：GluR 5 -7和KA-1-2（也分别称为谷氨酸受体离子型红藻氨酸盐（GRIK）1-5）。受体形成异三聚体或同源三聚体（仅GluR 5 -7）。GluR 5和GluR 6可以进行RNA编辑，从而改变通道对不同离子的渗透性。不同KAR亚基的细胞表面表达受受体转录物的选择性剪接和受体亚型的运输特性的调节。GluR 6基因位于染色体6q16.3-q21上，该区域已在几项双相情感障碍连锁研究中得到暗示。最近的遗传关联研究直接暗示GluR 6是增加情绪障碍风险的一个因素。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GluR 5和GluR 6敲除（KO）和野生型对照小鼠中进行了研究，使用情绪障碍和神经化学实验的行为测试电池。<br>GluR 5和6 KO小鼠似乎达到正常生长，并且没有神经异常。与WT和GluR 5 KO小鼠相比，GluR 6 KO消耗更多的糖精甜味剂溶液，这是享乐活动的指标。GluR 6 KO旅行更长的距离，进入并花费更多的时间在开放领域的中心（这可以作为一般活动以及探索性冒险活动的指标）。GluR 6 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竞技场的习惯。GluR 6 KO在社交互动和居民入侵者测试中都表现出攻击性。GluR 6 KO在高架十字迷宫的开放臂中具有更多的活性，而在强迫游泳测试中具有较少的不动性。GluR 6 KO在安非他明攻击试验中也表现出更高的反应。因此，GluR 6基因敲除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过度;这些似乎是临床躁狂状态的表型。此外，长期锂治疗减轻了GluR 6 KO小鼠的关键行为改变，包括提高运动活性，加重攻击性和对苯丙胺的超敏感性。神经化学实验没有发现任何显着的AMPA和NMDA受体的改变，但是，海马和前额叶皮层膜的GluR 5和KA-2受体的GluR 6基因敲除小鼠的水平下降，和慢性锂处理没有影响这些下降。总之，这些数据强烈支持GluR 6神经传递是情绪相关行为的关键调节剂的观点，并且GluR 6神经传递的遗传功能障碍可导致躁狂样行为的行为表现。未来的研究需要阐明人类GluR 6 SNP对GluR 6功能和相关神经传递的影响，参与GluR 6介导的情绪样行为可塑性的脑区，以及GluR 6作为开发情绪影响剂的新靶点。 由于担心抗抑郁药（SSRIs）可能与自杀想法和/或行为有关，特别是在儿童和青少年中，导致FDA对这些药物发出黑盒警告。这一警告导致了年轻人中SSRI处方的减少，同时这一人群中自杀率的增加，强调需要确定SSRI可能与这一人群中自杀意念相关的机制。最近的遗传学研究表明，GRIK 2基因（编码GluR 6红藻氨酸受体）赋予情绪障碍患者对治疗后出现的自杀意念的敏感性。此外，GRIK 2基因已被认为代表双极易感基因。值得注意的是，抗抑郁药可能对双相情感障碍患者有害，因为它们可能诱导周期加速，或引起激越/烦躁不安。考虑到这些和我们对GluR 6基因敲除小鼠的发现，我们假设GluR 6功能改变的小鼠（特别是青春期前小鼠）对SSRIs的反应会表现出这些行为水平的升高。 我们的初步数据表明，侵略水平随着年龄的增长，在所有GluR 6基因型（WT，HET和KO）组。与GluR 6 HET和WT小鼠相比，GluR 6 KO小鼠表现出更高的攻击行为。两周的西酞普兰治疗仅增加GluR 6 KO小鼠的攻击性，而不是WT小鼠。我们目前正在评估西酞普兰对GluR 6基因敲除小鼠的易怒和冲动行为的影响。