Function of glutamate delta-1 receptor

由谷氨酸三角洲1(GluD1)和谷氨酸三角洲2(GluD2)组成的Delta型谷氨酸受体家族是不寻常的，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的谷氨酸-小脑蛋白1(Cbln1)-Neurein复合体并诱导突触形成而被赋予突触生成特性。此外，Glud受体具有C-末端相互作用，这可能稳定突触后的密度机制，并有助于突触的可塑性。虽然GluD2亚单位在小脑平行纤维-浦肯野细胞突触的形成和可塑性中的作用已被证实，但在前脑中丰富的GluD2的作用仍不清楚。GluD1在纹状体中丰富，纹状体从皮质和丘脑接受强烈的兴奋性输入。我们的初步结果表明，GluD1在纹状体中等棘神经元的兴奋性神经传递中起着关键作用。我们的目标是在GluD1丢失后解决潜在的细胞类型和突触选择性的影响，这将支持它作为突触组织者的作用。我们将追求以下具体目标：(1)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，以及GluD1缺失对纹状体突触的影响和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。我们将使用传统的电生理学和体外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。我们将讨论纹状体GluD1缺失后突触功能的变化对纹状体回路调节的情绪、认知和运动行为的影响。这些研究将与DREADD技术相辅相成，以操纵特定的纹状体通路。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，并解决其在与神经精神和神经疾病相关的突触和行为表型中的作用。

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.