Function of glutamate delta-1 receptor

谷氨酸δ1受体的功能

• 批准号: 10411962
• 负责人: Shashank Manohar Dravid
• 金额: $ 22.11万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-03 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411962
• 关键词: 3-Dimensional; Ablation; Address; Affect; Agreement; Anxiety; Attention; Attention deficit hyperactivity disorder; Behavior; Behavior Control; Behavioral; Binding; Biochemistry; Bipolar Disorder; Brain; C-terminal; Cerebellum; Code; Cognitive; Cognitive deficits; Complement; Complex; Corpus striatum structure; Data; Deep Brain Stimulation; Developmental Delay Disorders; Disease model; Dorsal; Electron Microscopy; Electrophysiology (science); Emotional; Exhibits; Family; Frequencies; Functional disorder; Genes; Genetic study; Gilles de la Tourette syndrome; Glutamate Receptor; Glutamates; Goals; Huntington Disease; Immunohistochemistry; Knockout Mice; Lead; Ligands; Long-Term Depression; Maintenance; Mediating; Mental Depression; Mental disorders; Methods; Motivation; Motor; Mus; N-Methylaspartate; Neurodevelopmental Disorder; Neurons; Outcome; Parafascicular Nucleus; Parkinson Disease; Pathway interactions; Phenotype; Property; Prosencephalon; Purkinje Cells; Rett Syndrome; Role; Schizoaffective Disorders; Schizophrenia; Slice; Source; Structure; Structure of purkinje fibers; Synapses; Synaptic plasticity; System; Techniques; Thalamic structure; Therapeutic; Work; autism spectrum disorder; base; behavioral phenotyping; cell type; cognitive control; delta receptors; density; designer receptors exclusively activated by designer drugs; emotional behavior; flexibility; interdisciplinary approach; motor behavior; motor deficit; mouse model; nervous system disorder; neural circuit; neurocognitive disorder; neuropathology; neuropsychiatric disorder; neurotransmission; non-motor symptom; novel; novel therapeutics; optogenetics; postsynaptic; psychiatric symptom; receptor; synaptic function; synaptogenesis

The delta family of ionotropic glutamate receptors consisting of glutamate delta 1 (GluD1) and glutamate delta 2 (GluD2) are unusual since they do not exhibit typical ligand-gated ionic currents. Instead, they are endowed with synaptogenic property by forming a trans-synaptic GluD-Cerebellin1 (Cbln1)-Neurexin complex and inducing synapse formation. In addition, the GluD receptors have C-terminal interactions which may stabilize postsynaptic density machinery and contribute to synaptic plasticity. Although the function of GluD2 subunit in the formation and plasticity of parallel fiber- Purkinje cell synapse in the cerebellum is well established the role of GluD1 enriched in the forebrain remains largely unknown. GluD1 is enriched in the striatum which receives strong excitatory inputs from the cortex and thalamus. Our preliminary results demonstrate a critical role of GluD1 in excitatory neurotransmission in medium spiny neurons in the striatum. Our goal is to address potential cell-type and synapse-selectivity in this effect upon loss of GluD1 which will support its role as a synaptic organizer. We will pursue the following specific aims; (i) Determine the localization of GluD1 in the striatum and the effect of GluD1 loss on synaptic structure. We will use a range of complementary electron microscopy, immunohistochemistry and biochemistry methods to analyze distribution of GluD1 in the striatum and impact of GluD1 loss on striatal synapses and potential reorganization of synaptic components. (ii) Determine the role of GluD1 in synaptic neurotransmission and plasticity. We will use conventional electrophysiology together with ex vivo optogenetics to stimulate specific synapses to address potential synapse-specific roles of GluD1. (iii) Determine the role of striatal GluD1 in cognitive and behavioral control. We will address the impact of changes in synaptic function upon loss of striatal GluD1 on emotional, cognitive and motor behaviors that are regulated by striatal circuits. These studies will be complemented with DREADD technique to manipulate specific striatal pathways. Together, the proposed studies will systematically address the synaptic organizational principle of GluD1 in the striatum and address its role in synaptic and behavioral phenotypes relevant to neuropsychiatric and neurological disorders.

由谷氨酸δ 1 （GluD1）和谷氨酸δ 2 （GluD2）组成的三角洲家族是不寻常的，因为它们不表现出典型的配体门控离子电流。相反，它们通过形成跨突触GluD-Cerebellin1 (Cbln1)-Neurexin复合物并诱导突触形成而被赋予突触发生特性。此外，GluD受体具有c端相互作用，这可能稳定突触后密度机制并有助于突触可塑性。虽然GluD2亚基在小脑平行纤维-浦肯野细胞突触的形成和可塑性中的作用已经确定，但在前脑富集的GluD1的作用仍然很大程度上未知。GluD1在纹状体中富集，纹状体接收来自皮质和丘脑的强烈兴奋输入。我们的初步结果表明GluD1在纹状体中棘神经元的兴奋性神经传递中起关键作用。我们的目标是在GluD1缺失的情况下解决潜在的细胞类型和突触选择性，这将支持其作为突触组织者的作用。具体目标是：(i)确定GluD1在纹状体中的定位以及GluD1缺失对突触结构的影响。我们将使用一系列互补电镜，免疫组织化学和生物化学方法来分析GluD1在纹状体中的分布，以及GluD1丢失对纹状体突触和突触成分潜在重组的影响。（ii）确定GluD1在突触神经传递和可塑性中的作用。我们将使用常规电生理学和离体光遗传学来刺激特定突触，以解决GluD1在突触特异性中的潜在作用。（iii）确定纹状体GluD1在认知和行为控制中的作用。我们将探讨纹状体GluD1缺失后突触功能变化对纹状体回路调节的情绪、认知和运动行为的影响。这些研究将辅以DREADD技术来操纵特定纹状体通路。总之，拟议的研究将系统地解决纹状体中GluD1的突触组织原理，并解决其在神经精神和神经疾病相关的突触和行为表型中的作用。