Molecular mechanisms of human synapse formation induced by secreted bloodborne factors

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Synapses are unitary connections between neurons that enable rapid transfer and processing of information in the brain. Synapse formation is guided by two types of organizer molecules: adhesion molecules expressed at the neuronal cell surface and secreted factors produced inside the brain or externally by other organs. Of particular interest are "systemic factors" circulating in the bloodstream that have been shown to enhance learning and memory in mice. The goal of this research is to understand whether and how these systemic factors act on human neurons to regulate synapse formation. First, we will use human neurons derived from stem cells to screen structural proteins, growth factors and hormones for direct effects on synapse number and activity. This will be accomplished by treating the human neurons with each systemic factor and measuring changes in the activity of neuronal networks and in the synaptic responses of individual neurons to electrical stimulation. Second, we will combine biochemical and gene editing approaches to identify neuronal receptor proteins that bind to the systemic factors and elicit internal cellular responses to trigger synapse assembly and activity. Finally, we will generate human "mini-brain" organoids with a specialized tissue layer that forms a selective barrier between the internal organoid fluid and the external environment. We will test whether systemic factors can cross this selective barrier and examine potential effects on organoid synapse formation using high-resolution microscopy and global measurements of electrical network activity. Our mechanistic insights will establish a causal link between the systemic environment and brain function and may ultimately inform therapeutic strategies for neurodegenerative diseases driven by synapse loss.