We propose to examine the role of myosin VI in postsynaptic function and plasticity. Synaptic plasticity is the long-term modification of synaptic strength, which is linked to development, learning, and memory. Preliminary results suggest that myosin VI, a unique actin-based motor involved in endocytosis, is localized to synapses and enriched in the postsynaptic density (PSD). In addition, both myosin VI-disrupted hippocampal neurons and myosin VI mutant mice display synaptic abnormalities including decreased synaptic density and dendritic spine length, which may ultimately affect synaptic plasticity. To understand the role of myosin VI at the PSD, we propose to use both myosin VI-disrupted neurons and myosin VI mutant mice to explore deficits in synaptic density and morphology, glutamate receptor recycling, and synaptic plasticity, as assessed by both electrophysiology and dark-rearing experiments. Disruption of myosin VI has dramatic effects on the vestibular and auditory systems in mice and humans, suggesting its function is important and not redundant with other proteins. Myosin VI may be similarly critical for postsynaptic function and plasticity, deficits in which are seen in Down's syndrome, fragile X syndrome, and epilepsy.