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

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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.