Pre-Synapse to Nucleus Communication in Memory Function

突触或轴突末端的局部信号事件必须传递到细胞核以引起转录反应。神经元突起的长度对这种细胞内通信构成了重大挑战。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物等机制都可以应对这一挑战。后者包括越来越多的突触到核蛋白信使，其具有核定位信号，并且需要结合神经元输入素以进行长距离运输和核输入。神经元过程中的输入依赖性转运依赖于输入蛋白β1的局部翻译，并且可以在输入蛋白β1 3'UTR敲除小鼠中研究这些机制的扰动的功能后果。一系列的初步发现揭示了这种小鼠模型的记忆缺陷，非常有趣的是，这种缺陷似乎是突触前起源的。这一意想不到的有趣观察表明，突触前与核之间的通讯机制是通过输入蛋白β1实现的。本DFG项目申请将重点阐明importin β1在控制记忆的突触前位点中的功能作用的机制。该项目是两个实验室之间的真正合作，具有共同的科学兴趣和互补的专业知识，具有基础和转化意义。突触与核通讯是可塑性、学习和记忆机制的一个重要方面，因此这项研究将为大脑功能的基本方面提供重要的新见解。

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.