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 名儿童中约有 1 名患有自闭症谱系障碍 (ASD)，这给个人和家庭带来毁灭性后果，并造成经济负担。目前还没有针对自闭症谱系障碍的有效疗法，了解其潜在机制可能有助于识别新的治疗靶点。人类全基因组关联研究已经确定了可能导致自闭症谱系障碍的遗传变异。这些研究已经证实，自闭症谱系障碍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精确生理作用仍不清楚。 未知。 GRID1（谷氨酸受体离子型 Delta-1）基因编码谷氨酸 delta-1 (GluD1) 亚基，是一种被确定为自闭症谱系障碍 (ASD) 和分裂情感障碍的易感基因的基因。据报道，自闭症谱系障碍 (ASD) 和分裂情感障碍患者中 GluD1 表达较低。此外，最近的研究发现 GluD1 通过与突触前 Neurexin1 相互作用在突触形成中发挥潜在作用，而 Neurexin1 本身就是一种自闭症易感基因。这些一致的发现表明，GluD1 可能是自闭症谱系障碍中失调的功能性突触网络的一部分。我们的初步数据强烈表明，GluD1 的缺失会导致一些行为和分子异常，类似于人类 ASD 患者的缺陷。该提案的目标是专门了解 GluD1 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 GluD1 缺失对内侧前额叶皮质的脊柱形态和突触功能的影响，该功能调节已知会受到影响的社会行为和认知能力。 自闭症谱系障碍患者。我们还发现 NMDA 受体激动剂 D-环丝氨酸能够挽救 GluD1 基因敲除小鼠的社交缺陷。因此，我们将测试内侧前额叶皮层突触异常的逆转是否是 D-环丝氨酸治疗社交缺陷功效的基础。这些研究将为 GluD1 在调节突触结构和功能中的关键作用提供第一个证据，最终调节行为并可能确定 ASD 的新治疗靶点。此外，我们的研究将支持以下假设：促进活动依赖性机制可能对缓解 ASD 表型具有治疗价值。

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