Molecular Mechanisms Controlling Synapse Formation, Function and Stability: From Individual Synapses to Complex Neuronal Circuits.

Neuronal circuits are formed through synaptic connections between defined populations of neurons. The regulated assembly and disassembly of synaptic connections ensures precise connectivity during development and during plasticity of the mature circuit. In contrast, the inappropriate loss of synaptic connections leads to a disruption of neuronal circuits and to progressive neurodegenerative disorders. Therefore, identification of the molecular mechanisms controlling synaptic connectivity is essential for our understanding of neuronal circuit function and plasticity in development and disease.

We are combining two complementary systems to gain insights into the principles underlying synapse and neuronal circuit development. We use the Drosophila neuromuscular junction (NMJ) as a model system to identify the molecular and cellular mechanisms controlling synapse formation, function and stability at the level of individual synapses. To address how these synaptic mechanisms contribute to the assembly and function of neuronal circuits we use the adult taste circuit as a complementary model system.

At the NMJ we combine high resolution imaging assays with large-scale genetic screens to identify the molecular machinery controlling synaptic development in an unbiased manner. We then use state-of-the-art genetic, cellular and biochemical approaches together with super-resolution light and electron microscopy to understand the cellular dynamics controlling synapse assembly, function and maintenance. In the last years we identified a molecular network consisting of cell adhesion, cytoskeletal and regulatory molecules controlling the trans-synaptic regulation of synapse development and stability. These mechanisms are conserved throughout evolution and provided important new insights into the molecular mechanisms underlying nervous system development, learning and memory and neurodegenerative disease.

We use the adult taste circuit as a model system to identify the principles governing the development, function and plasticity of neuronal circuits. Here, sensory information is processed in central brain areas and then relayed to motoneurons to elicit a stereotypic behavior, the extension of the proboscis towards the food source. The selective genetic and physiological manipulation of individual neurons using thermo- and optogenetics allows the identification of molecular, cellular mechanisms underlying neuronal circuit formation and function. To elucidate the computational principles underlying taste processing and motor behavior we combine cellular and genetic manipulations with different behavioral tasks. Finally, we aim to address the relevance of synaptic connectivity and function using appetitive conditioning as a learning and memory assay.

Together these complementary approaches enable us to identify the cellular principles and mechanisms underlying synapse formation and plasticity with important implications for neuronal circuit function and ultimately animal behavior in development and disease.