Pre-Synapse to Nucleus Communication in Memory Function

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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.