Role of kalirin signaling in synaptic plasticity

Kalirin 信号在突触可塑性中的作用

• 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
• 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' 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

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）：该建议的目的是表征由蛋白质卡利林介导的机制，该蛋白质卡利林控制了锥体神经元中突触结构和功能可塑性。基于上一个赠款期间产生的数据，并使用我们最近生成的新型小鼠模型，我们将研究树突状脊柱可塑性的重要分子调节剂的作用。由于精神分裂症患者的大脑降低了脊柱密度和卡利林的表达，因此这些研究有望为精神疾病中脊柱病理学的机制提供重要的见解。修改多刺兴奋性突触结构和功能调节突触传播和可塑性，以及认知功能的基础。相反，改变的脊柱可塑性有助于几种精神障碍的发病机理。因此，了解控制刺突突触可塑性和病理学的分子机制将提供对影响认知的认知功能和精神障碍的神经生物学的基本见解。突触结构和功能由许多蛋白质之间的相互作用网络控制。我们先前的研究已将突触后蛋白卡利林（Kalirin）确立为突触结构可塑性的重要调节剂。重要的是，卡利林最近与包括精神分裂症在内的几种精神障碍有关。 Kalirin是一种脑特异性鸟嘌呤核苷酸交换因子，可激活小GTPase Rac1，其最丰富的形式Kalirin-7高度富集在棘中。在上一个资金期间，我们证明了Kalirin-7在NMDA受体和CAMKII的下游活动依赖性突触结构和功能可塑性中起重要作用。我们已经表明，卡利林还调节棘中的AMPA受体，并介导N-钙粘着蛋白依赖性的突触粘附信号传导。我们还产生了小鼠Kalrn基因（Kalrn - / - ）的完整敲除，并发现这会导致Rac1激活和功能性刺激突触的数量稳健和皮质特异性减少。 Kalrn - / - 小鼠在特定的认知功能方面具有损害。在此提案中，我们将剖析卡利林信号传导在多刺突触形态发生和可塑性中的功能作用。我们假设Kalirin信号传导在突触功能和脊柱稳定性/动力学中起着至关重要的特定作用。我们提出以下特定目的：1）表征AMPA受体介导的透射和可塑性的Kalirin依赖性调节的机制。 2）绘制时间过程并表征卡利林依赖性脊柱稳定性和动力学的机制。 3）表征kalirin信号在体内N-钙粘蛋白依赖性脊柱形态发生中的作用。 1 公共卫生相关性：该提案的目的是表征由控制锥体神经元中突触结构和功能可塑性的蛋白kalirin介导的机制。基于上一个赠款期间产生的数据，并使用我们最近生成的新型小鼠模型，我们将研究树突状脊柱可塑性的重要分子调节剂的作用。由于精神分裂症患者的大脑降低了脊柱密度和卡利林的表达，因此这些研究有望为精神疾病中脊柱病理学的机制提供重要的见解。 1