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名儿童中就有1名受到自闭症谱系障碍（ASD）的影响，对个人和家庭造成毁灭性后果沿着并成为经济负担。目前还没有有效的治疗方法可用于ASD和了解潜在的机制可能会导致识别新的治疗靶点。人类全基因组关联研究已经确定了可能导致ASD的遗传变异。这些研究已经确定ASD相关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。然而，几个新发现的候选基因的确切生理作用仍然是未知的。 未知GRID 1（谷氨酸受体离子型δ-1）基因编码谷氨酸δ-1（GluD 1）亚基，是一种被鉴定为ASD和情感障碍易感基因的基因。在ASD和情感性精神障碍患者中也报告了较低的GluD 1表达。此外，最近的研究已经确定了GluD 1通过与突触前Neurexin 1相互作用在突触形成中的潜在作用，Neurexin 1本身是自闭症易感基因。这些研究结果表明，GluD 1可能是ASD中失调的功能性突触网络的一部分。我们的初步数据有力地表明，GluD 1的缺失导致几种行为和分子异常，类似于人类ASD患者的缺陷。该提案的目标是具体了解GluD 1敲除小鼠中这些异常行为的神经基础。为此，我们将确定小鼠中GluD 1缺失对脊髓形态和内侧前额叶皮层突触功能的影响，该功能调节已知会影响的社会行为和认知能力。 ASD患者我们还发现，NMDA受体激动剂D-环丝氨酸能够拯救GluD 1敲除小鼠的社会缺陷。因此，我们将测试是否逆转内侧前额叶皮层的突触异常的基础上的疗效的D-环丝氨酸在社会赤字。这些研究将为GluD 1在调节突触结构和功能中的关键作用提供第一个证据，这些突触结构和功能最终调节行为，并可能确定ASD的新治疗靶点。此外，我们的研究将支持这一假设，即促进活动依赖性机制可能具有治疗价值，在减轻ASD表型。

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