Cell type-specific role of Homer proteins in synaptic plasticity

描述（由申请人提供）：兴奋性突触功能和结构的活动依赖性变化对神经回路的改变有重要贡献，神经回路的改变是许多形式的适应性和病理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经被认为在包括药物成瘾在内的各种大脑疾病中起着关键作用。因此，了解突触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适应不良的电路修改。哺乳动物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，这已经特别涉及疾病状态，是由第一组代谢型谷氨酸受体（mGluRs）的激活触发。与大多数G蛋白偶联受体一样，I组mGluRs受大分子蛋白复合物的严格调控，其中一个关键成分是支架蛋白Homer。Homer蛋白在多个水平调节I组mGluR的表达和功能，包括靶向、表面表达、聚集和与其他突触和突触下复合物的物理连接。在这个合作项目涉及美国实验室在斯坦福大学和印度实验室在印度科学教育和研究研究所在莫哈里，实验将进行，以解决的假设，荷马调控功能的特定组I mGluR，mGluR5，在同种型和细胞类型的具体方式。具体而言，荷马在调节mGluR5贩运和mGluR5触发的突触可塑性在海马CA1区锥体细胞和神经核中棘神经元使用分子操作结合电生理和成像分析的功能意义将被探讨。该项目的长期目标是测试mGluR5信号传导的Homer调节在药物诱发形式的行为可塑性中的作用，这些行为可塑性与成瘾的发展和维持有关。研究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，并将为开发更有效的治疗方法提供至关重要的发现。相关性药物成瘾涉及在某些关键大脑区域的神经细胞之间的物理连接（称为突触）的通信的长期修改。这个项目将使用复杂的实验技术来阐明这些突触修饰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。 公共卫生相关性：药物成瘾涉及到神经细胞之间的通信在其物理连接，这被称为突触，在某些关键的大脑区域的持久修改。这个项目将使用复杂的实验技术来阐明这些突触修饰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. PUBLIC HEALTH 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.