QnAs with Liqun Luo

To make us who we are, each of around 86 billion neurons has to find and connect with thousands of other neurons, forming the dense and complex network of the human brain. How is the precision of neuronal wiring achieved? Liqun Luo, a neurobiologist at Stanford University, investigates this question. Luo, who was elected to the National Academy of Sciences in 2012, uses the olfactory system of fruit flies (Drosophila melanogaster) to learn how neuronal circuits form. His Inaugural Article (1) reports the role of cellular growth factors and glial cells in shaping the specificity of neuronal wiring. Luo recently spoke to PNAS about his work.

Liqun Luo. Image courtesy of Liqun Luo.

PNAS: Why are you interested in the Drosophila olfactory system?

Luo: We are asking how neural circuits are assembled in developing brains. This is a long-standing developmental neurobiology question. The key interest in this is the wiring specificity. What determines how neurons connect specifically to their partners? How do you use a limited number of genes to wire up many more connections precisely? The olfactory system offers a very convenient experimental model.

There are 50 glomeruli [clusters of nerve endings] in each antenna lobe, the initial olfactory information processing station in the fly brain. Even though each glomerulus contains many hundreds or thousands of synapses, they are mostly the same kind because they relay information from the same type of the olfactory receptor neurons. Each type expresses the same odorant receptor and targets axons to the same glomerulus. Therefore, all of the information processed in a particular glomerulus is a particular type of information. Fifty discrete information-processing channels allow the flies to sense odors of biological significance, like food, pheromones, danger signals, et cetera. Each glomerulus is visible easily through light microscopy. Then, if there is any mistargeting—that is, if dendrites or axons of a neuron supposed to go to glomerulus 1 go to glomerulus 2—we can see that very easily. It’s synaptic specificity magnified.

PNAS: What is the question you address in your Inaugural Article (1)?

Luo: To have 50 glomeruli that are insulated from each other to relay specific information, you need to have discrete organization. Glia are nonneuronal cells. For a long time, they have been thought of as passive support cells, glues that hold the nervous system together. But recently, more and more evidence suggests there are many different types of glia, and each plays an important function. Ensheathing glia [one type of glial cell] make discrete compartments possible. If we get rid of the ensheathing glia, discrete compartments are disrupted and the wiring specificity is compromised. We want to understand how they help establish these compartments. How are they communicating with neurons?

PNAS: How is the Drosophila olfactory system organized?

Luo: There are three types of neurons in the olfactory system in this antenna lobe circuit. The first type is the olfactory receptor neurons. These are the neurons that receive information from periphery and project the axons to this place. The input neurons, you could call them. The second type is the output neurons, or projection neurons. These will send dendrites to these glomeruli individually and receive the input from these olfactory receptor neurons. They send output to the higher brain centers. The third type is local interneurons. These help information relay from input neurons to output neurons and reformat some of the information.

And then there are glia, two major types. One are the astrocytes. These are glia that invade into individual glomeruli and help maintain synaptic connections. The second are these ensheathing glia, which wrap outside of these individual compartments. The developmental sequence is that the output neurons initiate the antennal lobe patterning. They send dendrites into the antenna lobe first. Then, the input neuron sends axons that recognize dendrites of the output neurons. After their wiring specificity is pretty much established, the ensheathing glia begin to wrap around. We don’t think the glia are essential for the initial stages of wiring specificity. But they may be very important for the maintenance of this. Astrocytes come in even later.

PNAS: What are the key findings of your Inaugural Article (1)?

Luo: We have identified a signaling pathway involving fibroblast growth factors. These are secreted proteins, exported by cell A to tell cell B what to do. In this case, cell A, the neuron, makes the growth factors, and cell B, the ensheathing glia, will respond to it. This growth factor does at least two things. It tells the glia to wrap around individual glomeruli, and also maintains the survival of those glia. In the absence of either the growth factor or its receptor, there are fewer glial cells. We provided evidence that the survival of these glia required the growth factor.

Our experiments show that this signaling is instructive. We can overexpress, or produce more growth factor, in one specific glomerulus either by the input neurons or output neurons. And we find that that glomerulus becomes hyperwrapped by the glia. The signaling is also very local. The next glomerulus is not hyperwrapped.

PNAS: How do these results apply to human neurons?

Luo: These growth factors were found first in mammals. Both the growth factors and their receptors are highly conserved. These glia that wrap separate neuronal compartments are also present in humans, and also the human olfactory system is organized in a very similar way. You have these discrete compartments, except there are more of them because we have more types of olfactory receptor neurons.