Role of kalirin signaling in synaptic plasticity

Kalirin 信号在突触可塑性中的作用

基本信息

批准号：
8071572
负责人：
Peter Penzes
金额：
$ 36.1万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8071572
关键词：
AMPA Receptors Address Adhesions Adolescence Adult Affect Age Alzheimer&apos s Disease Attention deficit hyperactivity disorder Biochemical Brain Cell Adhesion Molecules Cell Culture Techniques Cognition Cognitive Complex Data Dendritic Spines Dependence Development Excitatory Synapse Functional disorder Funding Genes Genetic Grant Guanine Nucleotide Exchange Factors Human Impairment Knock-out Maintenance Mediating Mental disorders Modeling Modification Molecular Monomeric GTP-Binding Proteins Morphogenesis Morphology Mus N-Cadherin N-Methyl-D-Aspartate Receptors Neurobiology Neurons Pathogenesis Pathology Pathway interactions Patients Peptides Physiological Plasmids Play Preparation Proteins RNA Interference Reagent Regulation Regulatory Pathway Resources Role Schizophrenia Short-Term Memory Signal Transduction Staging Structure Synapses Synaptic Transmission Synaptic plasticity Techniques Time Validation Vertebral column age related brain remodeling calmodulin-dependent protein kinase II cognitive function density frontal lobe genome wide association study hippocampal pyramidal neuron in vivo insight mouse model multidisciplinary mutant novel postsynaptic public health relevance synaptic function transmission process

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to characterize the mechanisms mediated by the protein kalirin that control synaptic structural and functional plasticity in pyramidal neurons. Building upon data produced in the previous grant period, and using a novel mouse model we have recently generated, we will examine the role of an important molecular regulator of dendritic spine plasticity. As both spine density and kalirin expression are reduced in schizophrenic patients' brains, these studies are expected to provide important insight into the mechanisms of spine pathology in mental disorders. Modifications in spiny excitatory synapse structure and function modulate synaptic transmission and plasticity, and underlie cognitive functions. Conversely, altered spine plasticity contributes to the pathogenesis of several mental disorders. Hence, understanding the molecular mechanisms that control spiny synapse plasticity and pathology will provide essential insight into the neurobiology of cognitive functions and mental disorders that affect cognition. Synapse structure and function are controlled by a complex network of interactions between numerous proteins. Our previous studies have established the postsynaptic protein kalirin as an important regulator of synaptic structural plasticity. Importantly, kalirin has recently been implicated in several mental disorders including schizophrenia. Kalirin is a brain-specific guanine-nucleotide exchange factor which activates the small GTPase Rac1 and its most abundant form, kalirin-7, is highly enriched in spines. In the previous funding period we demonstrated that kalirin-7 plays an important role in activity-dependent synaptic structural and functional plasticity downstream of NMDA receptors and CaMKII. We have shown that kalirin also regulates AMPA receptors in spines, and mediates N-cadherin-dependent synaptic adhesion signaling. We have also generated a full knockout of the KALRN gene (KALRN-/-) in mice, and found that this results in a robust and cortex-specific reduction in Rac1 activation and in the number of functional spiny excitatory synapses. KALRN-/- mice have impairments in specific cognitive functions. In this proposal we will dissect the functional roles of kalirin signaling in spiny synapse morphogenesis and plasticity. We hypothesize that kalirin signaling plays crucial and specific roles in synapse function and spine stability/dynamics. We propose the following Specific Aims: 1) To characterize the mechanisms underlying kalirin-dependent regulation of AMPA receptor-mediated transmission and plasticity. 2) To chart the time course and characterize the mechanisms of kalirin-dependent spine stability and dynamics. 3) To characterize the role of kalirin signaling in N-cadherin-dependent spine morphogenesis in vivo. 1 PUBLIC HEALTH RELEVANCE: The objective of this proposal is to characterize the mechanisms mediated by the protein kalirin that control synaptic structural and functional plasticity in pyramidal neurons. Building upon data produced in the previous grant period, and using a novel mouse model we have recently generated, we will examine the role of an important molecular regulator of dendritic spine plasticity. As both spine density and kalirin expression are reduced in schizophrenic patients' brains, these studies are expected to provide important insight into the mechanisms of spine pathology in mental disorders. 1

描述（由申请人提供）：本提案的目的是表征由卡里林蛋白介导的控制锥体神经元突触结构和功能可塑性的机制。基于上一个资助期产生的数据，并使用我们最近生成的新型小鼠模型，我们将研究树突棘可塑性的重要分子调节剂的作用。由于精神分裂症患者大脑中的脊柱密度和 Kalirin 表达均降低，因此这些研究有望为精神障碍中脊柱病理机制提供重要的见解。多刺兴奋性突触结构和功能的改变调节突触传递和可塑性，并且是认知功能的基础。相反，脊柱可塑性的改变会导致多种精神疾病的发病机制。因此，了解控制刺突触可塑性和病理学的分子机制将为了解认知功能和影响认知的精神障碍的神经生物学提供重要的见解。突触结构和功能由众多蛋白质之间相互作用的复杂网络控制。我们之前的研究已经确定突触后蛋白 Kalirin 是突触结构可塑性的重要调节因子。重要的是，卡里林最近被发现与包括精神分裂症在内的多种精神疾病有关。 Kalirin 是一种大脑特异性鸟嘌呤核苷酸交换因子，可激活小 GTP 酶 Rac1，其最丰富的形式 Kalirin-7 在棘中高度富集。在之前的资助期间，我们证明了 Kalirin-7 在 NMDA 受体和 CaMKII 下游的活动依赖性突触结构和功能可塑性中发挥着重要作用。我们已经证明，kalirin 还调节棘中的 AMPA 受体，并介导 N-钙粘蛋白依赖性突触粘附信号传导。我们还在小鼠中实现了 KALRN 基因 (KALRN-/-) 的完全敲除，并发现这会导致 Rac1 激活和功能性多刺兴奋性突触数量的强劲和皮质特异性减少。 KALRN-/- 小鼠的特定认知功能存在障碍。在本提案中，我们将剖析 Kalirin 信号在多刺突触形态发生和可塑性中的功能作用。我们假设 Kalirin 信号在突触功能和脊柱稳定性/动力学中起着至关重要且特定的作用。我们提出以下具体目标：1）表征 AMPA 受体介导的传递和可塑性的 kalirin 依赖性调节的潜在机制。 2）绘制时间进程并表征依赖于kalirin的脊柱稳定性和动力学的机制。 3) 表征kalirin信号传导在体内N-钙粘蛋白依赖性脊柱形态发生中的作用。 1 公共健康相关性：该提案的目的是描述由卡里林蛋白介导的控制锥体神经元突触结构和功能可塑性的机制。基于上一个资助期产生的数据，并使用我们最近生成的新型小鼠模型，我们将研究树突棘可塑性的重要分子调节剂的作用。由于精神分裂症患者大脑中的脊柱密度和 Kalirin 表达均降低，因此这些研究有望为精神障碍中脊柱病理机制提供重要的见解。 1