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ABSTRACT

Neurons are highly specialized cells that face unique biological challenges to build our brains and nervous systems. To support rapid communication, neurons connect through synapses: specialized, asymmetric junctions capable of extremely fast signal transfer. Fundamentally, it is the location and properties of synapses that define the function of neural circuits and nervous systems. My research aims to determine molecularly how neurons build their synapses.

I have found that phase separation of core presynaptic scaffold molecules is a key mechanism in synapse formation. Biological phase separation is a phenomenon where proteins demix from the cytoplasm into dense, but fluid, condensates – a mechanism useful for concentrating and compartmentalizing cytoplasmic components. I found core active zone scaffold proteins, including SYD-2/Liprin-α, were capable of phase separation in vitro and in vivo at nascent synapses. Mutations that blocked phase separation resulted in defective synapse assembly and synaptic transmission, indicating phase separation is critical for synaptic development and function. Crucially, I found the defects were rescued when a phase separation motif from an unrelated protein was reintroduced into mutant SYD-2. Finally, I found presynaptic phase separation is activated through phosphorylation by the SAD-1 kinase, which relieves an autoinhibitory interaction within SYD-2. Together these results provide in vivo evidence that presynapses form through phase separation during development and indicate that condensate formation is a central assembly hub for synapse formation.

Host: Dr. Patrick McGrath