Role of kalirin signaling in synaptic plasticity

描述(申请人提供)：这项建议的目的是描述由Kalirin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。基于前一次资助期间的数据，并使用我们最近建立的一种新的小鼠模型，我们将检查树突棘可塑性的一个重要分子调节因子的作用。随着精神分裂症患者大脑中脊柱密度和Kalirin表达的减少，这些研究有望为精神障碍的脊柱病理机制提供重要的见解。刺状兴奋性突触结构和功能的改变调节突触的传递和可塑性，并构成认知功能的基础。相反，脊柱可塑性的改变导致了几种精神疾病的发病。因此，了解控制棘突突触可塑性和病理的分子机制将为了解影响认知的认知功能和精神障碍的神经生物学提供必要的见解。突触的结构和功能由众多蛋白质之间相互作用的复杂网络控制。我们以前的研究已经证实，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，卡利林最近被认为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，它激活小GTP酶rac1，其最丰富的形式Kalirin-7在脊椎中高度丰富。在之前的资助阶段，我们证明Kalirin-7在NMDA受体和CaMKII下游的活性依赖的突触结构和功能可塑性中发挥重要作用。我们已经证明Kalirin还调节脊髓中的AMPA受体，并介导N-钙粘附素依赖的突触黏附信号。我们还在小鼠中产生了KALRN基因(KALRN-/-)的完全敲除，并发现这导致rac1活性和功能性刺激性突触的数量显著减少，且特定于大脑皮质。KALRN-/-小鼠在特定的认知功能上有损害。在这个提案中，我们将剖析Kalirin信号在棘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/动力学中起着关键和特定的作用。我们提出了以下具体目标：1)研究Kalirin依赖调节AMPA受体介导的传递和可塑性的机制。2)绘制时间进程图并描述Kalirin依赖的脊柱稳定性和动力学的机制。3)研究Kalirin信号在体内N-钙粘素依赖的脊柱形态发生中的作用。1 公共卫生相关性：这项建议的目的是描述由Kalirin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。基于前一次资助期间的数据，并使用我们最近建立的一种新的小鼠模型，我们将检查树突棘可塑性的一个重要分子调节因子的作用。随着精神分裂症患者大脑中脊柱密度和Kalirin表达的减少，这些研究有望为精神障碍的脊柱病理机制提供重要的见解。1

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