STANFORD, Calif. - Critical connections that neurons form in the brain during development turn out to rely on common but overlooked cells, called glia. These cells were known to support the neurons in adults, but had never been fingered as players in forming the connections between neurons, known as synapses.
The Stanford University School of Medicine researchers who conducted the work, led by Ben Barres, MD, PhD, professor of neurobiology, also discovered two of the proteins made by glial cells that signal synapse formation. This study, published in the Feb. 11 issue of Cell, could help researchers understand diseases such as epilepsy and addiction in which too many synapses form.
"We knew glia had a close relationship with neurons," Barres said. "We never thought the synapses would entirely fail to form without the glia." In fact, that relationship was considered so unlikely that the grant application was turned down six times because the work was considered too risky. The research was eventually funded by the National Institute on Drug Abuse, whose interest in the work stems from the possibility that new synapses are what keep recovered addicts craving drugs.
Barres said the relationship remained hidden in past research because of the neuron's complete dependence on glial cells for survival in a lab dish. Nobody had ever succeeded in maintaining neurons without glial cells, so little was known about what the glial cells did, exactly.
However, in past work, Barres and his team devised a way of keeping the neurons alive without glial cells. In this environment the neurons formed one-seventh the number of synapses compared to cells grown with glia. He added that the glia probably have many additional roles, also unknown. "Ninety percent of human brain cells are glia and it's completely a mystery what they do," he said.
These previous experiments simply showed that the proteins glia secrete help neurons in a lab dish form synapses. What wasn't clear is which proteins, exactly, are responsible for the new synapses and whether glia perform the same role in the developing brain. The Cell paper addressed these questions.
Barres and his team found that when they added various glial proteins to neurons grown in a lab dish without glia, only two proteins, called thrombospondins, encouraged new synapses to form. However, the synapses aren't completely normal. The synapse is made from two neurons-one that sends the message and one that receives the message. On the sending side, the synapse appears normal, but the receiving end isn't able to detect signals. Barres said other as yet unidentified signals from glia are necessary to form fully functional synapses.
When the group created mice that lacked the two thrombospondins they found 40 percent fewer synapses on average than the normal counterparts.
These thrombospondins' role of encouraging synapses to form makes sense, given when they are present in the brain: Barres and his group found them in the brains of developing mice during the time that the brain is actively making new synapses.
Interestingly, recent studies have found that one of the two thrombospondins is found at far higher levels in adult human brains than in adult monkey brains, possibly suggesting a key difference in the two animals' ability to form new synapses.
Barres said the thrombospondins they studied are just two of five related proteins. So far it hasn't been possible to eliminate all five thrombospondins in mice, but he suspects what few synapses the mice eked out were thanks to the remaining thrombospondins or perhaps other glial proteins. "Had we been able to knock out all five we might have seen even more synapse loss," Barres said.
Figuring out how and why new synapses form could be a boon for doctors treating people with brain damage. "If we deliver thrombospondins in the adult brain we could potentially turn on synapse formation," Barres said.
People with epilepsy face the opposite problem. In this disease, the area of the brain where the epileptic attack originates contains both a mass of glial cells and neurons with excessive synapses. Barres suggested that the glial scar might have originally triggered the additional synapses to form. Learning more about how glia trigger synapse formation could help prevent the disabling condition.
Co-first authors on this paper were Karen Christopherson, PhD, postdoctoral fellow, and Erik Ullian, PhD, a postdoctoral fellow now at UCSF. Other Stanford researchers who contributed to this work are undergraduate students Caleb Stokes and Christine Mullowney.
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