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

穿孔通路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的神经元回路中的第一个突触。它们对记忆的形成很重要，因此具有多种突触可塑性机制。正如申请者最近所表明的，这些机制包括HCN1通道的年龄依赖性突触前表达。在第一个资助期，他们对突触可塑性的贡献进行了详细的研究，发现他们影响LTP和LTD的年龄依赖性。进一步发现，穿孔通路中HCN1的年龄依赖性轴突转运调控涉及rab8b相关蛋白TRIP8b亚型的差异表达。在第二个资助期，我们提出了旨在加深我们对这些机制的理解的实验。解决的问题包括：1)如何调节穿孔通路中TRIP8b异构体的表达？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）在通道的亚细胞运输中起什么作用？3) HCN1是否在穿孔通路中与其他可塑性相关的突触前蛋白（如mGluRs或Cav3.2通道）功能相互作用？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.