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1 Acta Neurobiologiae Experimentalis

1 2017

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Unconventional myosins as regulators of synaptic function and development

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Wagner W. , Lippmann K. , Alexander C. , Hammer III J. A. , Hornig S. , Freitag S. , Schonewille M. , Lombino F. , Roesler M. , Schwarz J. R. , De Zeeuw C. , Eilers J. , Kneussel M.

nr Suppl.1

Myosins are a large family of functionally diverse cytoskeletal motors that use actin filaments as tracks and that produce movement and force. Actin filaments are highly enriched within dendritic spines, the tiny postsynaptic compartments that carry excitatory synapses. By investigating the roles of unconventional myosins, we aim to shed light on the actin-dependent development and function of excitatory neuronal synapses. We employ cerebellar Purkinje cells (PCs) as a neuronal model system. Importantly, postsynaptic plasticity in these central cerebellar signal integrators appears to be crucial for motor learning. Interestingly, we were able to provide direct evidence that the processive class V myosin, myosin Va, is a point-to-point organelle transporter that moves endoplasmic reticulum as cargo into the dendritic spines of PCs. The spine endoplasmic reticulum supports local calcium signaling that is thought to be required for synaptic long-term depression at parallel fiber to Purkinje cell synapses (PF-PC LTD). We also examined the role of myosin VI, the only myosin known to move towards the minus end of the actin filament. Our data reveal that myosin VI affects AMPAR trafficking and dynamics in PCs. Importantly, we also find that myosin VI is crucial for postsynaptic function and plasticity of PCs. Nevertheless, myosin VI expression in PCs does not appear to be essential for motor coordination or cerebellum-dependent motor learning since myosin VI knock out specifically in PCs does not lead to impairments in this respect. Taken together, using cerebellar PCs as a model system, we are able to provide novel insights into the cellular mechanism of action of unconventional myosins and elucidate their roles for postsynaptic development and function. FINANCIAL SUPPORT: Marie Curie FP7 Integration Grant (PCIG11-GA-2012-321905) within the 7th European Union Framework Programme; DFG Research Unit FOR2419, project Wa3716/1-1; Landesforschungsförderung Hamburg FV27.