Overlooked brain cells may have leading role
A type of brain cell once thought to be little more than the neuron’s supportive sidekick may have a lead role in pruning the electrochemical connections that are crucial to brain development, learning, memory and cognition, a new study suggests.
Astrocytes, a type of glial cell, turn out to be veritable Pac-men, steadily gobbling up weak, extraneous and redundant synapses that are the vital link between neurons, according to a study published online Sunday in the journal Nature.
“Excess synapses are generated during development, and then they’re pruned back,” said Dr. Ben A. Barres, a neuroscientist at Stanford University School of Medicine. “Some synapses are selected, and survive, but a lot of synapses are just removed. But it wasn’t clear how that synapse elimination happened.”
That brain trimming has been made more clear, at least in a mouse visual circuit commonly used to study the human brain.
Barres has been focusing on glial cells – the name comes from the Latin word for glue – for three decades. “They’re very disrespected cells,” he said.
Over those years, Barres’ lab found found that without the star-shaped glial cells known as astrocytes, synapses fail to send strong signals. That only qualified glial cells for best-supporting-cell nominee, at most. But then Barr reported, in 2001, that neurons weren’t as good at creating new synapses without the astrocytes.
A growing number of neuroscientists have added to these findings and are suggesting that glial cells perform lead-actor role in shaping the brain’s signal-relaying architecture.
While figuring out how astrocytes affect synapse formation, Barres found that the cells had some intriguing genes – ones that turn it into a synapse destroyer.
“One of the most surprising things that we found was the astrocytes were very highly expressing several complete phagocytic pathways - they’re the cells that eat,” Barres said.
Postdoctoral researcher Won-Suk Chung, lead author of the current study, created experiments to test how that genetic pathway worked to trim a rodent’s lower-level visual circuitry in early stages of brain development. Synapses in that circuit must be eliminated so that each neuron from the retina connects with just one in the thalamus, which relays those signals to higher visual processing centers.
Chung showed that astrocytes surrounded and ingested functioning synapses via a chemical pathway centered on a pair of proteins coded by its Pac-man genes. Something about these proteins appeared to help the cell find a weak target.
The pair then showed how this activity varied at different stages of development and continued into adulthood.
If the same pruning of synapses can be demonstrated in human astrocytes, it could carry important implications for the battle against neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, for psychiatric disorders, and for the nagging loss of memory that comes with aging.
“Everyone is always assuming if there’s something wrong, the problem is in the neuron,” Barres said. “If the astrocytes are in the driver’s seat in terms of controlling synapse formation and synapse function, maybe those processes go awry in human disease.”
Barres’ lab had already shown that another type of glial cell – microglia – has a similar synapse digesting function, through a cascade of different proteins. He now suspects the two glia cells may strike a balance, perhaps targeting different types of synapses.
“The $64-million question is: how do the astrocytes and the microglia know which synapses to eat?” Barres said.
“In development, the evidence is that they’re eating all the right ones,” he added. “They’re eating the weak ones, the ones that formed in the wrong place. But what about in the adult brain? What if this process goes wrong and they now start eating good synapses, or synapses that shouldn’t be eaten? Could this lead to disease processes? If you have pathways that are overactive, could that lead to, say, a neuropsychiatric condition?”
Those questions, Barres said, will be pursued in future studies involving human brain cells.
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