Roles of kainate receptors in behavioral plasticity related to mood disorders

海人酸受体(KARs)是一类谷氨酸受体(GluRs)，对谷氨酸和γ-氨基丁酸(GABA)作出反应，调节与情绪调节有关的大脑区域的突触可塑性，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Ka1-2(也分别称为谷氨酸受体亲离子海藻酸(GRIK)1-5)。受体由形成受体通道的三聚体蛋白组成。GluRs 5和6可以进行RNA编辑，从而改变通道对不同离子的通透性。人类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)和野生型(WT)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。 <br> 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小鼠在这项享乐活动测试中摄入了更多的糖精甜味剂。GluR6 KO小鼠行走的距离更长，进入开阔场地中心的时间也更长，这是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，小鼠没有表现出对开阔场地的适应。GluR6 KO小鼠在社会互动和居民-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。GluR6 KO小鼠在苯丙胺激发试验中也表现出较高的反应性。因此，GluR6，而不是GluR5，KO小鼠表现出行为兴奋，更大的攻击性和快感；这些特征似乎与临床躁狂状态相似。此外，慢性锂治疗通过降低GluR6 KO小鼠增加的运动活动、加重的攻击性和对苯丙胺的超敏程度，缓解了关键的行为变化。神经化学研究没有发现谷氨酸受体亚型AMPA和NMDA的水平有任何显著变化；然而，GluR6 KO小鼠海马区和前额叶皮质膜GluR5和Ka-2受体水平下降，慢性锂治疗不影响这些下降。综上所述，这些数据有力地支持了这样的观点，即GluR6介导的神经传递是情绪相关行为的关键调节器，GluR6的遗传功能障碍可以导致躁狂样行为的行为表现。人类GluR6单核苷酸多态(SNPs)对GluR6相关神经传递的影响、参与GluR6修饰的行为可塑性的脑区以及GluR6作为控制情绪状态障碍的新的治疗靶点的作用还需要进一步的研究。 <br> 由于担心抗抑郁药(SSRI)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对这些药物发出黑箱警告。这一警告导致年轻人的SSRI处方减少，随之而来的是这一人群自杀率的上升，强调需要确定SSRI可能与自杀意念有关的机制。最近的遗传学研究表明，GRIK2基因(编码GluR6谷氨酸受体)使情绪障碍患者对治疗后出现的自杀念头具有敏感性。此外，GRIK2基因被认为是一种双相易感基因。值得注意的是，抗抑郁药可能对双相情感障碍患者有害，因为它们可能会导致周期加速或引起焦虑/烦躁不安。考虑到这些以及我们对GluR6 KO小鼠的发现，我们假设GluR6功能改变的小鼠(特别是青春期前小鼠)对SSRIs的反应将表现出这些行为水平的升高。我们的数据显示，在WT和GluR6 KO组中，攻击性水平都随着年龄的增长而增加。西酞普兰治疗两周会增加青春期前GluR6 KO小鼠的攻击性，但不会增加青春期前WT小鼠的攻击性。目前的研究旨在证实和推广初步发现。

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.