Assessment of glutamate delta-1 receptor in mental disorders

精神障碍中谷氨酸 delta-1 受体的评估

• 批准号: 8743273
• 负责人: Shashank Manohar Dravid
• 金额: $ 18.19万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8743273
• 关键词: 10q22.3; Affect; Agonist; Autistic Disorder; Behavior; Behavioral; Candidate Disease Gene; Child; Code; Cognitive; Cycloserine; Data; Dendritic Spines; Economic Burden; Exhibits; Family; Food Preferences; Frequencies; Genes; Genetic; Genetic Variation; Glutamate Receptor; Glutamates; Goals; Human; Human Genome; Hypersensitivity; Incidence; Individual; Knock-out; Knockout Mice; Label; Lead; Long-Term Potentiation; Medial; Mediating; Mental disorders; Modeling; Molecular; Molecular Abnormality; Morphology; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Outcome Study; Patients; Phenotype; Physiological; Planning Techniques; Prefrontal Cortex; Proteins; Recurrence; Regulation; Reporting; Research; Resistance; Reversal Learning; Role; Schizoaffective Disorders; Signal Pathway; Signal Transduction; Social Behavior; Social Interaction; Stereotyped Behavior; Stimulus; Structure; Surface; Susceptibility Gene; Symptoms; Synapses; Testing; Therapeutic; Time; Vertebral column; autism spectrum disorder; autistic behaviour; base; behavior test; density; effective therapy; genome wide association study; glutamate receptor delta 1; morphometry; neural circuit; new therapeutic target; novel; presynaptic; public health relevance; receptor function; relating to nervous system; social; social communication; synaptic function; synaptogenesis; vocalization

DESCRIPTION (provided by applicant): It is estimated that ~1 in every 110 children is affected by autism spectrum disorders (ASDs) with devastating consequence to the individual and family along with being an economic burden. There is currently no effective therapy available for ASD and understanding the underlying mechanisms may lead to identification of novel therapeutic targets. Human genome-wide association studies have identified genetic variations that may contribute to ASDs. These studies have established that ASD-associated genes are part of a large functional network involved in synapse formation and signaling. However, the precise physiological role of several of the newly identified candidate genes is still unknown. GRID1 (Glutamate Receptor Ionotropic Delta-1) gene, which codes for the glutamate delta-1 (GluD1) subunit, is one such gene identified as a susceptibility gene for ASDs and schizoaffective disorders. Lower GluD1 expression has also been reported in ASD and schizoaffective disorder patients. Moreover, recent studies have identified a potential role of GluD1 in synapse formation via interaction with presynaptic Neurexin1, which itself is an autism susceptibility gene. These converging findings suggest that GluD1 may be a part of the functional synaptic network that is dysregulated in ASD. Our preliminary data strongly indicates that deletion of GluD1 leads to several behavioral and molecular abnormalities that resemble deficits in human ASD patients. The goal of this proposal is to specifically understand the neural basis of these abnormal behaviors in GluD1 knockout mice. Towards this end we will determine the effect of GluD1 deletion in mouse on spine morphology and synaptic function in the medial prefrontal cortex, which regulates social behaviors and cognitive abilities known to be affected in ASD patients. We have also found that an NMDA receptor agonist D-cycloserine is able to rescue social deficits in GluD1 knockout mouse. We will therefore test whether reversal of synaptic abnormalities in the medial prefrontal cortex underlie the efficacy of D-cycloserine in social deficits. These studies will provide the first evidence for a crucial role of GluD1 in the regulation of synaptic structure and function that eventually modulate behavior and potentially identify a novel therapeutic target for ASD. Additionally, our studies will support the hypothesis that facilitation of activity-dependent mechanisms may have therapeutic value in alleviating ASD phenotype.

描述（由申请人提供）：据估计，每110名儿童中有〜1受自闭症谱系障碍（ASD）的影响，对个人和家人的毁灭性后果以及经济负担。目前尚无有效的ASD治疗，并且了解潜在机制可能会导致对新型治疗靶标的识别。人类基因组的关联研究已经确定了可能有助于ASD的遗传变异。这些研究已经确定，与ASD相关的基因是参与突触形成和信号传导的大型功能网络的一部分。但是，几个新确定的候选基因的精确生理作用仍然是 未知。 Grid1（谷氨酸受体离子Delta-1）基因，该基因编码为谷氨酸藻酸三核-1（GLUD1）亚基，是一种这样的基因，被鉴定为ASDS和SECHIZAISACTACTY障碍的易感基因。在ASD和精神分裂症患者中，还报道了较低的GLUD1表达。此外，最近的研究通过与突触前神经毒素的相互作用确定了GLUD1在突触形成中的潜在作用，该神经毒素本身就是一种自闭症易感基因。这些收敛的发现表明，GLUD1可能是ASD中失调的功能突触网络的一部分。我们的初步数据强烈表明，GLUD1的缺失导致几种行为和分子异常，它们类似于人ASD患者的缺陷。该提议的目的是特别了解GLUD1敲除小鼠这些异常行为的神经基础。为此，我们将确定glud1缺失对小鼠中内侧前额叶皮层中脊柱形态和突触功能的影响，从而调节社会行为和认知能力已知受到影响 ASD患者。我们还发现，NMDA受体激动剂D-Cycloserine能够挽救GLUD1敲除小鼠的社会缺陷。因此，我们将测试中间前额叶皮层中突触异常的逆转是否是D-胞克氏菌在社会缺陷中的疗效的基础。这些研究将为GLUD1在突触结构和功能调节中的关键作用提供第一个证据，这些证据最终调节行为并有可能确定ASD的新型治疗靶标。此外，我们的研究将支持以下假设：促进活动依赖性机制可能在减轻ASD表型方面具有治疗价值。

项目成果

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus.

谷氨酸 Delta-1 受体调节海马中代谢型谷氨酸受体 5 信号传导。

• DOI: 10.1124/mol.116.104786
• 发表时间: 2016
• 期刊: Molecular pharmacology
• 影响因子: 3.6
• 作者: Suryavanshi,PratyushS;Gupta,SubhashC;Yadav,Roopali;Kesherwani,Varun;Liu,Jinxu;Dravid,ShashankM
• 通讯作者: Dravid,ShashankM