QNAS QnAs with Ben Barres

Prashant Nair Science Writer

The density of cells in the human brain defies munologists, who had previously isolated imagination. Among the cellular throng, neu- different types of immune cells to study rons garner much of the credit for brain their functions and interactions. We found function. Viewed under the microscope, that astrocytes are not so passive after all: however, slices of brain tissue are crisscrossed In culture, they are polarized, electrically by swarms of cells of varying shapes. Collec- excitable, and make axons and dendrites, tively called glia, these cells enrobe neurons, just like neurons do. But they cannot form embrace blood vessels, envelop synapses, and synapses on their own. Importantly, our alter the chemical milieu in which the brain is ability to grow neurons and astrocytes sep- awash. As collaborators in brain function, arately allowed us to make the surprising glial cells were once considered a mildly fas- discovery that astrocytes secrete signals that cinating sideshow but have recently benefited are crucial for synapse formation, mainte- from a revival of intense scientific interest. nance, and function. Ben Barres, a neuroscientist at Stanford Uni- PNAS: More recently, you expanded the versity and the first transgendered researcher panoply of functions for astrocytes with an- to be elected to the National Academy of other finding: Astrocytes participate in synapse Sciences, has devoted a distinguished career elimination. Can you describe the significance to solving what he eloquently puts as “the of this role? mystery and magic of glia.” Over the years, Barres: During development, the brain Barres’ pursuit has helped redefine the scien- overproduces synapses, and the excess synap- Ben Barres. tific understanding of his favored cell type: ses are pruned during a window of devel- Far from being a janitorial workforce, glia, opment. Previously, we had shown that it turns out, control how synapses form, complement proteins [innate immune system learning and memory might in fact be tied function, and fade away, suggesting that these proteins involved in clearing pathogens and to astrocytes. resourceful cells might play a prominent role cellular debris] are associated with synapses Barres: Yes, we strongly suspect so. We are in activities commonly ascribed to neurons. throughout the central nervous system during now exploring whether the critical window The therapeutic implications of these find- the synapse-pruning window. That finding of developmental plasticity, when the brain ings are not lost on Barres, who explores suggested that complement might play a role undergoes early synaptic pruning, might be the potential of glia as drug targets in brain in synapse elimination, analogous to its im- under the control of an “astrocyte clock.” So diseases. Barres recently spoke to PNAS munological role in eliminating pathogens. it is possible—and this is our novel and about his interest in glia. Synapses coated with complement proteins intriguing hypothesis—that neuronal activity- PNAS: Over two decades, you have helped are recognized by microglia, which then clear dependent synapse pruning is in fact tied to revise the false notion of glia as the nervous the synapses. After brain development is com- the activation of astrocytes and their ability system’s lowly foot soldiers, whose raison pleted, the complement cascade is turned off, to gobble synapses. After all, astrocytes can d’être is to serve and support neurons. When presumably because the pruning is finished detect many kinds of neuronal signals, includ- did you become interested in glia? and circuits are stabilized. (As an aside, the ing neurotransmitters. Barres: I became interested in glia during complement cascade turns back on in neuro- PNAS: Have your findings on the func- my neurology training. As residents, we would degenerative diseases like Alzheimer’s. So the tions of glia led to the discovery of molecular look at diseased brain slices from patients untimely reactivation of synaptic pruning in drug targets? under the microscope. I was hooked by the the adult brain might contribute to such dis- Barres: We have shown that astrocytes se- dramatic morphological changes happen- eases.) We used the mouse retinogeniculate crete a signal called thrombospondin, which ing in glial cells in injured or diseased brain circuit, which is an elegant experimental sys- is necessary for synapse formation, and that tissues. Glia, astrocytes in particular, send tem to track synapses. In this circuit, we astrocytes also have a receptor for thrombo- out processes that make contact with major showed that astrocytes also actively engulf spondin. The pharmaceutical industry has blood vessels, but most astrocytes are clustered and eliminate synapses in a manner depen- been largely focused on neurons, but our around synapses. Backthen,itwasunclear dent on neuronal activity but independent finding suggests that glia might be important what astrocytes did in the brain, and the pre- of the complement proteins. We identified drug targets. The thrombospondin receptor vailing view was that they were passive sup- two other phagocytic pathways that the as- port cells for neurons. We purified neurons trocytes use to prune synapses. PNAS: This is a QnAs with a recently elected member of the National and glia and studied their interactions in So you are suggesting that neuronal Academy of Sciences to accompany the member’s Inaugural Article culture dishes, following the tradition of im- activity-dependent changes that occur during on page 10093.

10074–10075 | PNAS | August 18, 2015 | vol. 112 | no. 33 www.pnas.org/cgi/doi/10.1073/pnas.1512539112 Downloaded by guest on October 2, 2021 QNAS on neurons is also the receptor for the block- degeneration slow, which is formed by fusing Barres: The implications of these findings buster drug neurontin or gabapentin, used to parts of two different proteins, the axons are that if you administered a drug that treat pain and epilepsy. By showing that the were protected from degeneration after in- mimics Wlds during this therapeutic window receptor is necessary for thrombospondin to jury. This protection seems to be conserved after injury, you might be able to save axons induce excitatory synapse formation, including in several species; WldS promptly became a from degeneration. The metabolite NAD is synapses in pain circuits, and that neurontin potential drug target, but its mechanism was precisely such a drug candidate, and further antagonizes this interaction, we have uncovered unclear. So we tried to find out whether the studies will reveal how it might be used to a potential mechanism of action for the drug. protein turns on protective genes in the prevent axon degeneration. In addition, our findings on synapse pruning nucleus of the neuron or acts directly in PNAS: Your scientific work adds to the demonstrate that the classical complement the axon to protect it from degeneration. revisionist literature that has helped change cascade is an important target for neurodegen- To answer that question, my student Jack researchers’ regard for a long-neglected cell erative diseases, such as Alzheimer’sdisease. Wang used a technique developed here at type. You have also been a voluble spokes- PNAS: In your Inaugural Article (1), you person for other underrepresented entities in explore the phenomenon of axon degeneration, Stanford to control the stability and func- a common feature of many neurodegenerative tion of proteins in cells. He found that the science: women, for example. Would it be activity of WldS is required not in the nu- overreaching to infer a theme? diseases and injuries, focusing on the role of a Barres: protein that might hold a key to treating such cleus of the neurons but in the axons. Even Science proceeds at its best when diseases. Can you describe the protein? after the axons are severed, if WldS is sta- it includes diverse studies performed by Barres: There is a lot of interest in finding bilized in the axons, there is a window of diverse scientists. drugstosloworhaltaxonlossinthecentral four to five hours after injury when axonal nervous system. Several years ago, it was degeneration can be blocked. PNAS: 1 Wang JT, Medress ZA, Vargas ME, Barres BA (2015) Local axonal shownthatinmutantmicethatproduceda What do these findings mean for protection by Wlds as revealed by conditional regulation of protein chimeric protein called WldS, or Wallerian the treatment of nerve damage? stability. Proc Natl Acad Sci USA 112:10093–10100.

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