kmatsuda.z7@keio.jp

Understanding Life through Cell–Cell Connections

How Do Neurons Know Where to Connect?

One of the experiences that first drew me to synapses was visualizing Purkinje cells in the cerebellum of a transgenic mouse using a fluorescent protein. I was struck by the beauty of their highly branched dendrites. Their surface was covered with countless tiny protrusions called dendritic spines, where neurons receive input from other neurons.

Looking at these structures raised a simple question: among so many cells and so many possible sites, how does a neuron know where to connect? Moreover, not all synapses are the same. Different connections contain different sets of molecules and have distinct functional properties.

What You Connect Determines the Identity of a Synapse

This question led me to study the molecules that organize synaptic connections. In 2010, using cultured cells and mice, we showed that Cbln1, a secreted protein in the cerebellum, binds to the receptor GluD2 and induces synapse formation. I later extended this work to the hippocampus, where in 2016 we found that the secreted proteins C1ql2/3 recruit specific kainate-type glutamate receptors to particular synapses and thereby shape their characteristic signaling properties.

These studies suggested that secreted proteins do more than simply hold neurons together. Which molecules are connected across the extracellular space can determine which proteins are recruited to a synapse and what kind of functional connection is formed. We consider this to be one of the molecular principles underlying synaptic diversity.

This idea also reminded me of a conversation I had as a graduate student. At the time, I was studying genes regulated by growth factors, and a colleague and I talked about why secreted proteins were particularly interesting: because they act outside the cell, their effects could potentially be controlled simply by adding them from the outside.

“If adding a molecule from the outside can change cell function, that already sounds a little like a drug.”

Years later, Cbln and C1ql turned out to be exactly this kind of extracellular molecule. This led to another question: if extracellular molecules can organize synaptic connections, can we use the same principle to build connections ourselves?

We are now developing artificial molecules that bridge selected proteins on cell surfaces. By choosing which proteins to connect, we aim not only to study how synapses are formed, but also to create, modify, or restore specific neuronal connections.

From Synapses in the Brain to Connections between Nerves and Organs

Our studies of synapses have raised a broader question: are the molecular principles that organize neuron–neuron connections also used when neurons interact with other cell types?

Throughout the body, neurons communicate not only with other neurons but also with epithelial, immune, endocrine, and other cells. How are these specialized sites of communication formed? How does a neuron select its cellular partner? And how does forming a connection change the state and function of the cell on the other side?

We are now addressing these questions in peripheral neural systems, including somatosensory and enteric circuits. Rather than simply asking which cells are located next to neurons, we want to understand the molecular mechanisms that organize these interfaces and how communication across them affects cellular states and organ function.

By applying the molecular analysis and connection-manipulation approaches developed through our studies of central synapses, we aim to understand cell–cell connections across different biological scales: from molecular organization at individual contact sites, to changes in cellular state, and ultimately to the regulation of organ function.