Deciphering the Roles of Kainate Receptors in Developing CNS Circuits

解读红藻氨酸受体在发展中枢神经系统回路中的作用

• 批准号: 10385827
• 负责人: Anis Contractor
• 金额: $ 51.72万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385827
• 关键词: Ataxia; Behavior; Behavioral; Brain region; Child; Childhood; Chlorides; Cognitive; Communication; Comparative Study; Contractor; Corpus striatum structure; Data; Dendrites; Development; Developmental Delay Disorders; Disease; Equilibrium; Etiology; Exhibits; Face; Genes; Genetic; Genetic Diseases; Glutamate Receptor; Goals; Hippocampus (Brain); Homeostasis; Human; Human Genetics; Intellectual functioning disability; Kainic Acid Receptors; Knock-out; Knowledge; Laboratories; Lead; Long-Term Effects; Measures; Mediating; Missense Mutation; Modeling; Molecular; Molecular Analysis; Morphology; Motor; Mus; Mutant Strains Mice; Mutation; Nature; Neuraxis; Neurodevelopmental Disorder; Neurologic; Neurons; Neurotransmitter Receptor; Phenotype; Photometry; Physiological; Play; Population; Property; Proteome; Proxy; Receptor Gene; Receptor Signaling; Regulation; Role; Shapes; Signal Transduction; Social Interaction; Structure; Symptoms; Synapses; Synaptic Transmission; Testing; Variant; autism spectrum disorder; base; behavioral phenotyping; behavioral study; causal variant; cellular development; cognitive function; critical period; developmental disease; experimental study; genetic variant; human model; in vivo; insight; interest; loss of function; loss of function mutation; motor disorder; mouse model; nervous system development; neurodevelopment; neuron development; neuronal circuitry; neuronal excitability; neurotransmitter release; receptor function; social; stereotypy; synaptic function

SUMMARY Kainate receptor signaling is required for the appropriate development of the central nervous system. Children with de novo loss-of-function or missense mutations exhibit intellectual disability and other severe developmental phenotypes. Why this occurs is unknown, in part because we do not have a clear understanding of how aberrant kainate receptor function disrupts neural development. The objectives of this project are to (i) gain insight into normal neurodevelopmental roles played by kainate receptors and (ii) to determine the nature of circuit and behavioral disruptions when kainate receptor signaling is aberrant or completely lost in mouse models. We will pursue these objectives using comparative studies in mice that model known genetic variants causative for human disorders. These include a new mouse line generated in the Swanson laboratory, GluK2(A657T), that models a human de novo missense mutation in the Grik2 gene that causes intellectual disability (ID) and ataxia, as well as mice which model Grik2 haploinsufficiency which is associated with developmental delay and ID in human populations. The Contractor, Swanson and Savas laboratories will use these mice to test the hypotheses that kainate receptors establish an appropriate balance between excitation and inhibition in developing hippocampal circuits, are required for correct development of synapses, and regulate intrinsic excitability in the CNS. In the first Specific Aim, we will determine how missense or loss-of-function mutations in Grik2 alter synaptic connectivity, function, morphology and expression of the synaptic and non-synaptic proteome in brain regions associated with altered behaviors. In the second Specific Aim, we determine how intrinsic excitability is altered in kainate receptor mutant mice. In the third Specific Aim, we will carry out behavioral studies on kainate receptor mutant mice to determine the expanse of cognitive, social, habitual, and motor dysfunction, which will also inform the physiological studies in Aims 1 and 2. We anticipate these studies will reveal some of the underlying circuit disruptions that give rise to human cognitive and motor phenotypes. We therefore aim to develop a comprehensive and integrated understanding of the importance of kainate receptor signaling to establishment of appropriate neuronal function in the CNS and establish how aberrant signaling leads to maladaptive development and behaviors in mice that are correlates of the core symptoms of human developmental disorders.

概括 红藻氨酸受体信号传导是中枢神经系统正常发育所必需的。孩子们 从头开始功能丧失或错义突变表现出智力障碍和其他严重的 发育表型。为什么会发生这种情况尚不清楚，部分原因是我们没有明确的 了解异常的红藻氨酸受体功能如何破坏神经发育。本次活动的目标 项目的目的是（i）深入了解红藻氨酸受体发挥的正常神经发育作用，以及（ii） 当红藻氨酸受体信号传导异常或时，确定电路和行为中断的性质 完全迷失在小鼠模型中。我们将通过对小鼠的比较研究来实现这些目标 建立导致人类疾病的已知遗传变异模型。其中包括生成的新鼠标线 Swanson 实验室 GluK2(A657T)，模拟人类 Grik2 基因中的从头错义突变 导致智力障碍 (ID) 和共济失调的小鼠，以及模拟 Grik2 单倍剂量不足的小鼠 与人类发育迟缓和智力障碍有关。承包商、斯旺森和萨瓦斯 实验室将使用这些小鼠来测试红藻氨酸受体建立适当平衡的假设 发育中海马回路的兴奋和抑制之间的关系是正确发育所必需的 突触，并调节中枢神经系统的内在兴奋性。在第一个具体目标中，我们将确定如何 Grik2 的错义或功能丧失突变会改变突触连接、功能、形态和 与行为改变相关的大脑区域中突触和非突触蛋白质组的表达。在 第二个具体目标是，我们确定红藻氨酸受体突变小鼠的内在兴奋性是如何改变的。在 第三个具体目标，我们将对红藻氨酸受体突变小鼠进行行为研究，以确定 认知、社交、习惯和运动功能障碍的范围，这也将为生理学研究提供信息 目标 1 和 2。我们预计这些研究将揭示一些导致 人类认知和运动表型。因此，我们的目标是开发一个全面、综合的 了解红藻氨酸受体信号转导对于建立适当的神经元功能的重要性 并确定异常信号传导如何导致小鼠适应不良的发育和行为 与人类发育障碍的核心症状相关。

项目成果

The Antiseizure Drug Perampanel Is a Subunit-Selective Negative Allosteric Modulator of Kainate Receptors.

抗癫痫药物吡仑帕奈是红藻氨酸受体的亚基选择性负变构调节剂。

• DOI: 10.1523/jneurosci.2397-21.2022
• 发表时间: 2022
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Taniguchi,Sakiko;Stolz,JacobR;Swanson,GeoffreyT
• 通讯作者: Swanson,GeoffreyT

Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.

• DOI: 10.1016/j.ajhg.2021.07.007
• 发表时间: 2021-08
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: Jacob R. Stolz;Kendall M. Foote;H. Veenstra-Knol;R. Pfundt;S. T. ten Broeke;N. de Leeuw;Laura Roht