Pre-Synapse to Nucleus Communication in Memory Function

突触或轴突终末的局部信号事件必须传递到细胞核才能引发转录反应。神经元突起的长度对这种细胞内交流构成了巨大的挑战。应对这一挑战的机制从钙波中编码的快速信号到分子马达携带的较慢的大分子信号复合体。后者包括越来越多的突触到核的蛋白信使，这些信使含有核定位信号，需要结合神经元输入蛋白进行长途运输和核输入。神经元突起中的Importin依赖的运输依赖于Importinβ1的局部翻译，这些机制的扰动的功能后果可以在Importinβ1 3‘Utr基因敲除小鼠中进行研究。一系列初步发现揭示了这种小鼠模型的记忆缺陷，非常有趣的是，这些缺陷似乎源于突触前。这一意想不到和有趣的观察表明，通过Importinβ1实现了突触前到核的通信机制。这个DFG项目的应用将专注于阐明Importinβ1在突触前部位控制记忆的潜在功能作用的机制。该项目是两个实验室之间的真正合作，两个实验室拥有共同的科学兴趣和互补的专业知识，具有基本和翻译意义。突触到核的通讯是可塑性、学习和记忆机制的一个关键方面，因此这项研究将为大脑功能的关键方面提供新的关键线索。

Local signaling events at synapses or axon terminals must be communicated to the nucleus to elicit transcriptional responses. The lengths of neuronal processes pose a significant challenge for such intracellular communication. This challenge is met by mechanisms ranging from rapid signals encoded in calcium waves to slower macromolecular signaling complexes carried by molecular motors. The latter include a growing number of synapse-to-nucleus protein messengers that harbor a nuclear localization signal and require binding of neuronal importins for long-distance transport and nuclear import. Importin-dependent transport in neuronal processes is dependent on local translation of importin β1, and functional consequences of perturbation of these mechanisms can be studied in an importin β1 3’UTR knockout mouse. A series of preliminary findings have revealed memory deficits in this mouse model, and very intriguingly the deficits appear to be of presynaptic origin. This unexpected and intriguing observation suggests a presynapse-to-nucleus communication mechanism via importin β1. This DFG project application will focus on elucidating the mechanisms underlying functional roles of importin β1 in presynaptic sites controlling memory. The project is a true collaboration between two laboratories with shared scientific interest and complementary expertise, and with both basic and translational significance. Synapse to nucleus communication is a critical aspect of plasticity, learning and memory mechanisms, and this research will therefore shed critical new light on essential aspects of brain function.