MEREMY6 · Uncovering the mechanism and physiological relevance of myosin-VI-dependent AMPA receptor trafficking in neurons.

The proper trafficking of membranes and associated proteins in neurons is crucial for the function of the nervous system. Myosin-VI is an actin-based cytoskeletal motor that promotes membrane trafficking and is suggested to play crucial roles in neurons. Most notably, the myosin affects the intracellular trafficking of AMPA receptors, major neurotransmitter receptors composed of transmembrane protein subunits. In addition, data suggest a potential link between myosin-VI and neurodegenerative diseases such as Alzheimer’s. Here, we want to dissect the molecular mechanism by which myosin-VI acts in AMPA receptor trafficking in neurons. Furthermore, we aim to determine the relevance of myosin-VI-driven AMPA receptor trafficking events for structure, function and plasticity of a well-characterized neuronal circuit, and for behavioral output. To this end, we will focus on Purkinje neurons as a model system. These cerebellar neurons are crucial for the coordination and fine-tuning of movements and for certain forms of motor learning. We will make use of genetically altered mice in combination with approaches such as transfection and live cell microscopy of cultured Purkinje neurons, in vitro genetic rescue experiments, ultra-structural analyses via electron microscopy, electrophysiological methods and behavioral tests. We expect that our study will provide novel, general insights into the mechanism by which myosin-VI functions in membrane trafficking. In particular, the results should shed new light onto the molecular and cellular events that take place in Purkinje neurons and determine output from the cerebellum. Moreover, understanding the mechanism of function of neuronal myosin-VI might impact our view of the pathogenesis of neurodegenerative disease.