Role of kalirin signaling in synaptic plasticity

描述（由申请人提供）：本提案的目的是表征由蛋白质kalirin介导的控制锥体神经元中突触结构和功能可塑性的机制。建立在前一个赠款期间产生的数据，并使用一种新的小鼠模型，我们最近产生的，我们将研究树突棘可塑性的一个重要的分子调节器的作用。由于精神分裂症患者大脑中的脊柱密度和kalirin表达均降低，这些研究有望为精神障碍中脊柱病理学机制提供重要见解。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，并成为认知功能的基础。相反，脊柱可塑性的改变有助于几种精神疾病的发病机制。因此，了解控制棘突触可塑性和病理学的分子机制将为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。突触的结构和功能由许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建立了突触后蛋白kalirin作为一个重要的调节突触结构可塑性。重要的是，卡林最近与包括精神分裂症在内的几种精神疾病有关。Kalirin是一种脑特异性鸟嘌呤核苷酸交换因子，可激活小的GTdR Rac 1，其最丰富的形式Kalirin-7高度富集在棘中。在之前的资助期间，我们证明了kalirin-7在NMDA受体和CaMKII下游的活性依赖性突触结构和功能可塑性中起着重要作用。我们已经表明，卡林还调节AMPA受体在脊柱，介导N-钙粘蛋白依赖性突触粘附信号。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Rac 1激活和功能性多刺兴奋性突触数量的稳健和皮质特异性减少。KALRN-/-小鼠在特定的认知功能方面存在障碍。在这个提议中，我们将剖析卡林信号在棘状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。我们提出以下具体目的：1）表征Kalirin依赖的AMPA受体介导的传递和可塑性调节的机制。2)绘制时间过程并表征卡林依赖性脊柱稳定性和动力学的机制。3)描述Kalirin信号在体内N-钙粘蛋白依赖性棘形态发生中的作用。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