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Uncovering the mechanism and physiological relevance of myosin-VI-dependent AMPA receptor trafficking in neurons.

Final Report Summary - MEREMY6 (Uncovering the mechanism and physiological relevance of myosin-VI-dependent AMPA receptor trafficking in neurons.)

The cellular mechanisms that govern synaptic function and development in the nervous system are still incompletely understood. We aim to shed light on these mechanisms by dissecting the role of myosin VI in the transport of neurotransmitter receptors. Myosin VI is a cytoskeletal motor that moves towards the minus end of the actin filament and that is involved in intracellular membrane trafficking events such as clathrin-mediated endocytosis, exocytosis and autophagy. Moreover, myosin VI is implicated in the trafficking of AMPA receptors which are crucial neurotransmitter receptors that mediate fast neurotransmission at excitatory synapses. Our objectives in the project comprised to uncover the precise mechanism via which the myosin affects AMPA receptor trafficking. Moreover, we aimed to determine the significance of neuronal myosin VI for synaptic function and plasticity and for cerebellar motor learning. To address these points, we made use of Snell's waltzer mice that carry a functional null allele of Myo6, the gene encoding the myosin VI heavy chain. Our data show that AMPA receptor-mediated synaptic transmission and synaptic plasticity are impaired in cerebellar Purkinje cells of these mice. This suggests that myosin VI-dependent AMPA receptor trafficking in Purkinje cells is crucial for synaptic function. Using mice that carry a conditional knockout of the myosin, we tested whether this protein is required in Purkinje cells for motor learning and coordination. Our data currently suggest that this is not the case. To obtain insight into how myosin VI might act in regulating synaptic AMPA receptor numbers in Purkinje cells, we characterized its cellular and subcellular localization in brain. Furthermore, we developed novel tools that allow us to investigate which of the myosin's biophysical properties and protein interactions are crucial for AMPA receptor trafficking in neurons. In summary, our findings shed new light on the mechanisms that regulate synaptic function and emphasize the relevance of myosins in this fundamentally important process.