Function of glutamate delta-1 receptor

谷氨酸δ1受体的功能

基本信息

批准号：
10176185
负责人：
Shashank Manohar Dravid
金额：
$ 37.61万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-03 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176185
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

项目摘要

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.

由谷氨酸三角洲1（GLUD1）和谷氨酸三角洲2（GLUD2）组成的离子型谷氨酸受体的三角洲家族是不寻常的，因为它们没有表现出典型的配体门控离子电流。取而代之的是，它们通过形成反式突触Glud-cerebellin1（CBLN1） - 纽苏素复合物并诱导突触的形成来赋予它们具有突触的特性。另外，GLUD受体具有C末端相互作用，可以稳定突触后密度机制并有助于突触可塑性。尽管Glud2亚基在小脑中平行纤维Purkinje细胞突触的形成和可塑性中的功能已经很好地确定了Glud1在前脑中的作用仍然很大。 Glud1富集在纹状体中，从皮质和丘脑接收强烈的兴奋性输入。我们的初步结果表明，GLUD1在纹状体中棘神经元中兴奋性神经传递中的关键作用。我们的目标是在这种影响GLUD1的影响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。我们将追求以下特定目标；（i）确定Glud1在纹状体中的定位以及Glud1损失对突触结构的影响。我们将使用一系列互补的电子显微镜，免疫组织化学和生物化学方法来分析GLUD1在纹状体中的分布和GLUD1损失对纹状体突触的影响以及突触成分的潜在重组。（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以及离体光遗传学来刺激特定的突触，以解决GLUD1潜在的突触特异性作用。（iii）确定纹状体GLUD1在认知和行为控制中的作用。我们将解决突触功能变化对纹状体GLUD1的丧失对受纹状体回路调节的情绪，认知和运动行为的影响。这些研究将与Dreadd技术相辅相成，以操纵特定的纹状体途径。拟议的研究将共同解决纹状体中GLUD1的突触组织原理，并解决其在与神经精神疾病和神经系统疾病有关的突触和行为表型中的作用。