Project Details
Projekt
From imprecise synapse seeding to robust synapse formation by stabilization mechanisms of early molecular scaffolds
Subject Area
Developmental Neurobiology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 453877723
The addition of new synaptic connections is a process fundamental to the development and function of synaptic circuits. However, how a developing neuron controls the number, placement and strength of individual synaptic release sites is poorly understood. In particular, the dynamics and control points that ultimately steer synapse assembly are unknown and challenging to study in most in vivo systems. The developing Drosophila larval neuromuscular junction offers a model where the probabilistic dynamics of synapse assembly can be studied live and in real time over the course of several hours. We here have pioneered intravital imaging of synapse assembly at the molecular and subcellular levels and previously shown that the outcome of this developmental process is a stoichiometrically well-defined pre-postsynaptic protein architecture, precondition for robust functionality. Synaptic function is robust to the developmental variability of neuromuscular morphology and synaptic arrangement. During development, Liprin-a clusters kick-off (“seed”) the assembly process of nascent active zones, while components specific for mature active zones follow considerably later. Notably, Liprin-a clusters display a highly fluctuating behavior characterized by probabilistic stabilization or disassembly. In P1, we seek to understand how the probabilistic nature of synapse assembly leads to functionally robust NMJ structure and function. We hypothesize that Liprin-a clusters are subject to several, testable influences that determine the fate of each synaptic seeding event individually, including the dynamics and availability of proteins required for synaptic assembly as well as cell-non-autonomous trans-synaptic signals required for the stabilization of nascent synapses. In preparation for RobustCircuit, we have identified genetic inroads to manipulate and test molecular mechanisms controlling nascent synapse dynamics. Based on our analysis of the synapse seeding process, we will have established a model for the development of functional robustness based on dynamic and probabilistic decision-making processes at the level of molecular synapse assembly.
DFG Programme
Research Units
