The purpose of our research is to understand the mechanisms of synapse development and homeostasis. The chemical synapse is the fundamental communication unit connecting cells in the nervous system to one another and to non-neuronal cells, and designed to mediate rapid and efficient transmission of signals across the synaptic cleft. This transmission forms the basis for the biological computations that underlie and enable our complex behavior. Crucial to this function is the ability of a synapse to change its properties, so it can optimize its activity and adapt to the status of the cells engaged in communication and/or to the larger network comprising them. Consequently, synapse development is a highly orchestrated process coordinated by intercellular communication between the pre- and postsynaptic compartments, and by neuronal activity itself. Our long-term goal is to elucidate the molecular mechanisms that regulate , particularly those involving cell-cell communication, that regulate formation of functional synapses during development, and fine-tune them during plasticity and homeostasis. We focus on two related questions: 1) how are tissues patterned and correctly connected by long-range signals, and 2) how cells structures and functions are coordinated at short-range with those of their neighbors. BMPs modulate long-range signaling during patterning, but also ensure short-range communication at specialized cell-cell interaction zones, for example the neuromuscular junction (NMJ). Through studies on extracellular modulators of BMP signaling we aim to elucidate mechanisms that shape cell-cell communication during early patterning and at NMJ synapses.In recent years we have initiated a groundbreaking project to understand the mechanisms of synapse assembly using the Drosophila NMJ as a genetic model. Drosophila NMJ is a glutamatergic synapse, similar in structure and physiology to mammalian central AMPA/Kainate synapses. In flies, each NMJ is unique and identifiable, synapses are large and accessible for electrophysiological and optical analysis, making the Drosophila NMJ a favorite genetic system to study synapse development. The three key processes in synaptogenesis: (1) trafficking of components to the proper site, (2) organizing those components to build synaptic structures, and (3) maturation and homeostasis of the synapse to optimize its activity. Our laboratory addresses the mechanisms underlying these processes using a comprehensive set of approaches including genetics, biochemistry, molecular biology, super resolution imaging and electrophysiology recordings in live animals and reconstituted systems. We use a powerful genetics system, Drosophila melanogaster, and the neuromuscular junction (NMJ) as a model for glutamatergic synapse development and function.
In flies, the subunits that form the glutamate-gated ion channels (iGluRs) are known and relatively well studied. Howevercharacterized, but the molecular mechanisms that control iGluRs clustering and stabilization at postsynaptic densities remain a mystery. We have discovered a novel, essential protein, Neto (Neuropillin and Tolloid-like), that is absolutely required for iGluRs clustering at the Drosophila NMJ. Neto is the first auxiliary protein described in Drosophila and is the only non-channel subunit required for functional glutamate receptors. These findings provide an entry point to understand the molecular mechanisms of synapse developmentthe synaptic recruitment of iGluRs have remained unknown for decades. We discovered an essential auxiliary protein, Neto, absolutely required for the iGluR clustering and NMJ functionality. The discovery of Neto allowed us to reconstitute functional NMJ iGluRs in heterologous systems and to characterize the biophysical properties of Drosophila iGluRs. In recent studies we report presynaptic Neto functions crucial for basal neurotransmission and synapse homeostasis and describe a novel BMP signaling modality that stabilizes selective iGluRs as a function of their activity. Our screens for Neto interacting partners uncovered novel molecules critical for synapse development thus revealing a Neto-coordinated network that organizes and fine-tunes synapse structure and function. Our studies will provide a temporal and spatial description of the molecular events and pathways that shape the assembly, maturation and development of synaptic junctions.
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