Cell type-specific role of Homer proteins in synaptic plasticity

描述(申请人提供)：兴奋性突触功能和结构中依赖活动的变化对神经回路的改变有重要贡献，神经回路是许多形式适应性和病理性经验依赖性可塑性的基础。事实上，适应不良或功能失调的突触可塑性已被认为在包括药物成瘾在内的各种脑功能障碍中发挥关键作用。因此，了解影响突触可塑性和经验依赖性可塑性的分子机制将为了解正常回路提供重要的见解。 功能，以及导致大脑紊乱的不适应电路修改。哺乳动物的大脑表达几种不同形式的突触可塑性，具有不同的触发和表达机制。其中几个与疾病状态有关，是由I组代谢性谷氨酸受体(MGluRs)激活触发的。像大多数G蛋白偶联受体一样，I组mGluRs受到一个大分子蛋白复合体的严格调控，其中一个关键成分是支架蛋白Hmer。Homer蛋白在多个水平上调节I组mGluRs的表达和功能，包括靶向、表面表达、聚集以及与其他突触和突触下复合体的物理连接。在这个合作项目中，斯坦福大学的一个美国实验室和莫哈里的印度科学教育与研究所的一个印度实验室将进行实验，以解决这样的假设，即荷马以一种异构体和细胞类型特定的方式调控特定的I组mGluR，mGluR5的功能。具体地说，荷马在调节mGluR5转运和mGluR5触发的海马CA1锥体细胞和伏隔核中棘神经元突触可塑性中的功能意义将被结合电生理和成像分析来探索。该项目的长期目标是测试荷马对mGluR5信号的调节在药物诱发的行为可塑性形式中的作用，这些可塑性与成瘾的发展和维持相关。这一结果将为成瘾等大脑疾病的大脑机制研究开辟新的创新领域，并将提供对开发更有效的治疗方法至关重要的发现。相关性药物成瘾涉及神经细胞之间在其物理连接上的长期通信改变，这种联系被称为突触，在某些关键的大脑区域。这个项目将使用复杂的实验技术来阐明这些突触修改发生的一些关键分子机制。将收集的信息对于开发更有效的成瘾和其他相关大脑疾病的治疗方法至关重要。

DESCRIPTION (provided by applicant): Activity-dependent changes in excitatory synaptic function and structure importantly contribute to the modifications in neural circuitry that underli many forms of adaptive and pathological experience-dependent plasticity. Indeed, maladaptive or dysfunctional synaptic plasticity has been proposed to play a critical role in a variety of brai disorders including drug addiction. Thus understanding the molecular mechanisms contributing to synaptic and experience-dependent plasticity will provide important insights into normal circuit function as well as the maladaptive circuit modifications that underlie brain disorders. The mammalian brain expresses several different forms of synaptic plasticity with distinct triggering and expression mechanisms. Several of these, which have been specifically implicated in disease states, are triggered by activation of group I metabotropic glutamate receptors (mGluRs). Like most G-protein coupled receptors, group I mGluRs are tightly regulated by a macromolecular protein complex, a key component of which is the scaffolding protein Homer. Homer proteins regulate the expression and function of group I mGluRs at multiple levels including targeting, surface expression, clustering, and physical linkage to other synaptic and subsynaptic complexes. In this collaborative project involving a US laboratory at Stanford University and an Indian laboratory at the Indian Institute of Science Education and Research in Mohali , experiments will be performed to address the hypothesis that Homers regulate the function of the specific group I mGluR, mGluR5, in an isoform- and cell type-specific manner. Specifically, the functional significance of Homer in regulating mGluR5 trafficking and mGluR5-triggered synaptic plasticity in hippocampal CA1 pyramidal cells and nucleus accumbens medium spiny neurons using molecular manipulations combined with electrophysiological and imaging assays will be explored. The long-term goal of this project is to test the roles of Homer modulation of mGluR5 signaling in drug-evoked forms of behavioral plasticity of relevance to the development and maintenance of addiction. The results will open up new, innovative areas of research on the brain mechanisms underlying brain disorders such as addiction and will provide findings that are critical for the development of more effective treatments. Relevance Drug addiction involves long-lasting modification of the communication between nerve cells at their physical connections, which are termed synapses, in certain key brain areas. This project will use sophisticated experimental techniques to elucidate some of the key molecular mechanisms by which these modifications of synapses occur. The information that will be collected is essential for the development of more effective treatments for addiction and other related brain disorders.