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: 7978816
• 负责人: MILES A. HERKENHAM
• 金额: $ 12.43万
• 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/7978816
• 关键词: Acceleration; Adolescent; Affect; Age; Aggressive behavior; Agitation; Amphetamines; Amygdaloid structure; Anterior; Antidepressive Agents; Behavior; Behavioral; Behavioral Genetics; Bipolar Disorder; Boxing; Brain region; Butyric Acids; Child; Chromosomes; Chronic; Citalopram; Clinical; Data; Disease; Drug Delivery Systems; Etiology; Exhibits; Family; Feeling suicidal; Functional disorder; Future; Genes; Genetic; Glutamate Receptor; Glutamates; Goals; Growth; Hippocampus (Brain); Human; Hyperactive behavior; Individual; Ions; Kainic Acid Receptors; Knock-out; Knockout Mice; Lithium; Manic; Mediating; Membrane; Mood Disorders; Moods; Motor Activity; Mus; N-Methylaspartate; Neurologic; Patients; Permeability; Pharmaceutical Preparations; Phenocopy; Population; Proteins; RNA Editing; Risk; Risk-Taking; Role; Saccharin; Selective Serotonin Reuptake Inhibitor; Single Nucleotide Polymorphism; Social Interaction; Solutions; Susceptibility Gene; Swimming; Synaptic plasticity; Testing; Therapeutic; Time; Travel; Upper arm; behavior test; cingulate cortex; dysphoria; genetic association; genetic linkage; hedonic; indexing; interest; kainate; mood regulation; neurochemistry; neurotransmission; new therapeutic target; novel; prepuberty; receptor; research study; response; suicide rate; trait

Kainate receptors (KARs) represent a class of glutamate receptors (GluRs) that respond to glutamate and gamma-amino-butyric acid (GABA) and regulate synaptic plasticity in brain regions involved in mood regulation, including the anterior cingulate cortex, hippocampus, and amygdala. The KAR family includes five subunits: GluR 5-7 and KA 1-2 (also called glutamate receptor ionotropic kainate (GRIK) 1-5 respectively). The receptors comprise trimeric proteins that form the receptor channel. GluRs 5 and 6 can undergo RNA editing, resulting in altered channel permeability to different ions. The human GluR6 gene is located on chromosome 6q16.3-q21, a region of which has been implied in several bipolar disorder linkage studies. Recent genetic association studies directly implicate 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 wildtype (WT) 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 mice consumed more saccharin-sweetened solution in this test of hedonic activity. GluR6 KO mice traveled longer distances, entered and spent more time in the center of the open field, which serves as an index for explorative risk-taking activities. The hyperactivity of GluR6 KO persisted throughout the entire experimental period, and the mice showed no habituation to the open-field arena. GluR6 KO mice 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 mice also exhibited higher responses in amphetamine challenge test. Thus, GluR6, but not GluR5, KO mice display behavioral excitement, greater aggressiveness, and hyperhedonia; these traits appear to phenocopy the clinical manic state. Furthermore, chronic lithium treatment relieved key behavioral alterations of GluR6 KO mice by reducing the levels of heightened locomotor activity, aggravated aggression, and supersensitivity to amphetamine. Neurochemical studies did not reveal any significant alterations in levels of the glutamate receptor subtypes called AMPA and NMDA; 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-mediated neurotransmission is a critical modulator of mood related behavior and that genetic dysfunction of GluR6 can result in behavioral display of mania-like behavior. Future studies are needed to elucidate the effects of human GluR6 single nucleotide polymorphisms (SNPs) on GluR6-related neurotransmission, brain regions involved in GluR6-mdiated behavioral plasticity, and GluR6 as a novel therapeutic target for controlling mood state disorders. <br> 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 suicide rates in this population, emphasizing the need to identify the mechanisms whereby SSRIs may be associated with suicidal ideation. Recent genetic studies show that the gene GRIK2 (which encodes for the GluR6 glutamate 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 data show that aggression levels increased with age in both WT and GluR6 KO groups. Citalopram treatment for two weeks increased aggression in the prepubertal GluR6 KO mice, but not in the prepubertal WT mice. Current studies are aimed at confirming and extending the preliminary findings.

红藻氨酸受体（KAR）代表一类谷氨酸受体（GluR），其响应谷氨酸和γ-氨基丁酸（GABA）并调节涉及情绪调节的脑区域（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）。受体包括形成受体通道的三聚体蛋白。GluRs 5和6可以进行RNA编辑，从而改变通道对不同离子的渗透性。人类GluR 6基因位于染色体6q16.3-q21，在一些双相情感障碍连锁研究中已经暗示了该区域。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（WT）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小鼠在该享乐活性测试中消耗更多的糖精甜味溶液。GluR 6基因敲除小鼠在空旷场地的中心行进了更长的距离，进入并花费了更多的时间，这是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，并且小鼠没有表现出对开放场地竞技场的习惯。GluR 6基因敲除小鼠在社会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基因敲除小鼠在安非他明攻击试验中也表现出更高的反应。因此，GluR 6，而不是GluR 5，KO小鼠表现出行为兴奋，更大的侵略性，和快感;这些特征似乎表现为临床躁狂状态。此外，慢性锂治疗减轻了GluR 6基因敲除小鼠的关键行为改变，降低了运动活动的水平，加重了攻击性，对苯丙胺的超敏感性。神经化学研究未发现谷氨酸受体亚型AMPA和NMDA水平的任何显著变化;然而，GluR 6 KO小鼠海马和前额叶皮质膜GluR 5和KA-2受体水平降低，长期锂处理不影响这些降低。总之，这些数据强烈支持GluR 6介导的神经传递是情绪相关行为的关键调节剂的观点，并且GluR 6的遗传功能障碍可以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单核苷酸多态性（SNPs）对GluR 6相关的神经传递，大脑区域参与GluR 6介导的行为可塑性，以及GluR 6作为控制情绪状态障碍的新治疗靶点的影响。 <br> 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。这一警告导致年轻人的SSRI处方减少，同时这一人群的自杀率增加，强调需要确定SSRI可能与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谷氨酸受体）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。我们的数据表明，攻击水平随着年龄的增长，在WT和GluR 6 KO组。西酞普兰治疗两周增加了青春期前GluR 6 KO小鼠的攻击性，但在青春期前WT小鼠中没有。目前的研究旨在确认和扩展初步研究结果。