The blood–brain barrier is playing a critical role in controlling the influx and efflux of biological substances essential for the brain’s metabolic activity as well as neuronal function. While the role of the blood-brain barrier has long been appreciated, very little is known about how the cells that form the barrier influence the function of the nervous system. Now researchers at the Buck Institute for Research on Aging have uncovered a new role for these cells.

The findings are published in the journal the Proceedings of the National Academy of Sciences (PNAS) in an article titled, “Delta/Notch signaling in glia maintains motor nerve barrier function and synaptic transmission by controlling matrix metalloproteinase expression.”

“While the role of barrier function in establishing a protective, nutrient-rich, and ionically balanced environment for neurons has been appreciated for some time, little is known about how signaling cues originating in barrier-forming cells participate in maintaining barrier function and influence synaptic activity,” wrote the researchers. “We have identified Delta/Notch signaling in subperineurial glia (SPG), a crucial glial type for Drosophila motor axon ensheathment and the blood-brain barrier, to be essential for controlling the expression of matrix metalloproteinase 1 (Mmp1), a major regulator of the extracellular matrix (ECM).”

“What we know currently about the blood-brain barrier is mostly that we don’t know much beyond the basics,” said Buck Institute professor Pejmun Haghighi, PhD.

The finding introduces a new approach to looking for therapies that could counter damage caused by neurodegenerative diseases.

The team used fruit fly larvae for their study. The investigation began with a focus on enzymes called metalloproteinases because of their potential to be critical in interactions between glia and neurons. The team identified a pathway that is known as Notch signaling.

“We weren’t planning on studying Notch, but we found it was the main player in the maintenance of the blood-brain barrier,” said Haghighi. They discovered that Notch signaling in glia regulates the overall structure of the barrier. When the signal is blocked, not only is barrier function impaired, but the “fundamental work of the nervous system is affected,” he said, including neurotransmitter release and muscle contractions.

“Because we are seeing disruption in barrier function, without any obvious leakiness of the barrier, having an effect on synaptic function, this is a conceptual advance,” he said, as no one had observed cells from the barrier itself controlling neuron activity before.

“We can’t say what is cause and what is effect yet, but we can say that it is beyond just a correlation that some patients have breakdown of blood-brain barrier: it is an important defect associated with neurodegeneration,” Haghighi said.

Their findings open up a completely different perspective for developing novel therapeutics aimed at countering damage in barrier function related to neurodegenerative diseases.

“We are hoping that we can work backward to understand overall what the relationship is between the blood-brain barrier and neurodegenerative diseases,” Haghighi said. “We are exploring all these signaling pathways to see if we can translate our findings from larval synaptic function to more of a universal age-dependent model of neurodegeneration.”