Präsynaptische HCN-Kanäle im Hippokampus: Regulation des axonalen Transports und synaptische Metaplastizität

在穿通径轴突和齿状回颗粒细胞之间形成的突触构成了连接内嗅皮层和海马区的神经元环路中的第一个突触。它们对记忆的形成很重要，因此被赋予了突触可塑性的各种机制。正如申请人最近所表明的那样，这些机制包括年龄相关的HCN1通道的突触前表达。在第一个资助期，详细研究了它们对突触可塑性的贡献，发现它们对LTP和LTD的影响是年龄相关的。进一步发现，穿孔通路中HCN1的年龄依赖性轴突运输的调节涉及到与Rab8b相关的蛋白TRIP8b的不同亚型的表达。对于第二个资助期，我们建议进行旨在加深我们对这些机制的理解的实验。涉及的问题包括：1)TRIP8b亚型在穿透通路中的表达是如何调节的？2)HCN1的翻译后修饰，如泛素化或与分类连接蛋白SNX3的相互作用，对通道的亚细胞运输起着什么作用？3)HCN1在穿通通路中是否与其他可塑性相关的突触前蛋白相互作用，如mGluRs或Cav3.2通道？我们相信，回答这些问题将大大加深我们对HCN1调控的了解，从而进一步了解穿支通路中的突触可塑性。

Synapses formed between perforant path axons and dentate gyrus granule cells constitute the first synapses in a neuronal loop connecting entorhinal cortex and hippocampus. They are important for memory formation and therefore endowed with a variety of mechanisms for synaptic plasticity. As the applicants have recently shown, these mechanisms include an age-dependent presynaptic expression of HCN1 channels. During the first funding period, their contribution to synaptic plasticity was examined in detail, and it was found that they affect LTP as well as LTD age-dependently. It was further found that regulation of the age-dependent axonal transport of HCN1 in perforant path involves the differential expression of isoforms of TRIP8b, a Rab8b-associated protein. For the second funding period, we propose experiments designed to deepen our understanding of these mechanisms. Questions addressed include: 1) How is the expression of TRIP8b isoforms in perforant path regulated? 2) What roles play posttranslational modifications identified for HCN1, such as ubiquitination or interaction with the sorting nexin SNX3, for the subcellular trafficking of the channels? 3) Does HCN1 functionally interact with other plasticity-related presynaptic proteins in perforant path, such as mGluRs or Cav3.2 channels? We believe that answering these questions will substantially further our knowledge of HCN1 regulation, and thus of synaptic plasticity, in the perforant path.