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.

海藻酸盐受体（KARS）调节参与情绪调节的不同大脑区域的谷氨酸和GABA的释放，包括前夹层皮层，海马和杏仁核。 KAR家族包括五个亚基：GLUR5-7和Ka-1-2（也称为谷氨酸受体离子旋转Kainate（Grik）1-5）。该受体形成抗三聚体或同二聚体（仅GLUR5-7）。 GLUR5和6可以进行RNA编辑，从而导致对不同离子的通道渗透性改变。不同KAR亚基的细胞表面表达受受体转录本的替代剪接和受体亚型的运输特性调节。 GLUR6基因是在6q16.3-Q21染色体上，在几种双相情感障碍链接研究中隐含了一个区域。最近的遗传关联研究直接暗示GLUR6是增加情绪障碍风险增加的因素。但是，海谷酸酯受体在情绪调节中的作用在很大程度上是未知的。因此，我们使用行为测试电池对情绪障碍和神经化学实验进行了对GLUR5和GLUR6基因敲除（KO）和野生型对照小鼠进行的研究。<br> Glur5和6 KO小鼠似乎实现了正常生长，并且缺乏神经学异常。与WT和GLUR5 KO小鼠相比，GlUR6 KO消耗了更多的糖精甜味溶液，这是享乐活动的指标。 Glur6 Ko走得更长，进入并花了更多时间在空旷的中心（这可以作为一般活动的指数以及探索风险的活动）。在整个实验期间，GLUR6 KO的多动症一直持续存在，他们对开放式竞技场没有任何习惯。 GLUR6 KO在社交互动和居民 - 企业测试中都表现出侵略性。 GlUR6 KO在高架迷宫的开放臂中具有更多的活动，而在强制游泳测试中的固定性较小。 GLUR6 KO在苯丙胺挑战测试中也表现出更高的反应。因此，glur6而不是glur5，ko小鼠在整个实验中表现出行为兴奋，更大的侵略性和超卫生症。这些似乎是临床躁狂状态的表情。此外，慢性锂治疗缓解了GlUR6 KO小鼠的关键行为改变，包括增强的运动活性，对苯丙胺的加重侵略性和超敏反应。神经化学实验并未揭示AMPA和NMDA受体的任何显着改变，但是，GLUR6 KO小鼠的GlUR5和Ka-2受体的海马和前额叶皮质膜水平降低，慢性锂治疗不会影响这些降低。综上所述，数据强烈支持以下观点：glur6神经传递是情绪相关行为的关键调节剂，而glur6神经传递的遗传功能障碍可以导致躁狂样行为的行为表现。需要未来的研究来阐明人Glur6 SNP对GlUR6和相关神经传递功能的影响，与GlUR6相关的GLUR6涉及的类似情绪的行为可塑性以及GlUR6作为发展情绪影响剂的新目标。 担心抗抑郁药（SSRI）可能与自杀思维和/或行为有关，尤其是在儿童和青少年中，导致FDA对这些药物发出黑匣子警告。警告导致年轻人的SSRI处方减少，并随之增加了该人群的自杀性，强调需要确定SSRIS可能与该人群自杀念头有关的机制。最近的遗传研究表明，基因Grik2（编码Glur6海藻酸盐受体）赋予了对情绪障碍患者中对治疗伴随的自杀意念的敏感性。另外，已建议GRIK2基因代表双相敏感性基因。值得注意的是，抗抑郁药可能对躁郁症患者有害，因为它们可能诱导循环加速或引起搅动/烦躁不安。考虑到这些和我们使用GlUR6 KO小鼠的发现，我们假设具有改变GLUR6功能的小鼠（尤其是前小鼠）将表现出这些行为水平升高，这是对SSRIS的反应。 我们的初步数据表明，在所有GLUR6基因型（WT，HET和KO）组中，攻击水平随着年龄的增长而增加。与GlUR6 HET和WT小鼠相比，Glur6 KO小鼠的攻击行为升高。两周的西妥位治疗只会增加GLUR6 KO的攻击性，但不增加WT小鼠。我们目前正在评估西妥位丙酰基对GLUR6 KO小鼠易怒和冲动行为的影响。