Molecular Mechanisms of Synapse Assembly and Plasticity

The major goal of the research in our lab is to understand the mechanisms by which synapses are formed and modified. In the nervous system, the elemental means of communication between cells is synaptic transmission. Essential to the high speed and efficiency by which neurons communicate is the exquisite molecular organization of the pre- and postsynaptic apparatus. At the presynaptic compartment, neurotransmitter-laden vesicles are poised at active zones, ready for immediate release, and the calcium channels necessary for triggering exocytosis are spatially linked to the secretory machinery. At the postsynaptic membrane, neurotransmitter receptors form high-density clusters which are directly apposed to the active zones. Thus, proper development and functioning of synaptic junctions requires positional information, which coordinates the correct placement of pre- and postsynaptic elements. Once synapses are formed, it is the ability of synaptic connections to strengthen or to weaken which is believed to be central to the processes of learning and memory, and the restoration of synaptic connectivity after a traumatic injury.

In the lab we are using a multidisciplinary approach that includes genetics, confocal and electron microscopy, electrophysiology and molecular biology to identify the proteins required to scaffold the synapse and to regulate it's molding during plasticity. Much of our studies are carried out using a Drosophila glutamatergic synapse model that has a high degree of evolutionary conservation with excitatory synapses in the mammalian brain. Using these approaches we have identified several proteins with fundamental roles in synapse formation and synapse dynamics, including Dlg, a member of the PSD-95 family, Wingless, a well-recognized factor for early embryonic pattern formation but with novel roles in synapse development, and APPL, the fly homolog of human APP, a protein with key roles in the development of Alzheimer's disease. This approach is proving to be extremely powerful in elucidating the cell biological mechanisms by which neuronal cell communication is established and modulated.