When astrocytes overproduce a protein called ephrin-B1, the ability to retain memory weakens, University of California, Riverside, researchers report.

Glial cells surround neurons and provide support — not unlike hospital staff and nurses supporting doctors to keep operations running smoothly. These often-overlooked cells, which include oligodendrocytes and astrocytes, are the most abundant cell types in the central nervous system.

“We examined mouse learning behaviors and found that overproduction of this protein in astrocytes can lead to impaired retention of contextual memory and the ability to navigate in space. We think that astrocytes expressing too much of ephrin-B1 can attack neurons and remove synapses, the connections through which neurons communicate,"

said Iryna Ethell, a professor of biomedical sciences in the School of Medicine, who led the research. Such synapse loss is seen in neurodegenerative disorders such as Alzheimer’s disease, amyotrophic lateral sclerosis, and multiple sclerosis.

Synapse Remodeling

When Ethell and colleagues examined mouse cell behavior in a petri dish, they found astrocytes were “eating up” synapses when ephrin-B1 was overexpressed, suggesting that glial-neuronal interactions influence learning.

“The overproduction of ephrin-B1 can be a novel mechanism by which unwanted synapses are removed in the healthy brain, with excessive removal leading to neurodegeneration,"

Ethell said.

While the research was done on a mouse model, the results are applicable in humans whose astrocytes also produce ephrin-B1. Astrocytes tend to increase ephrin-B1 production during traumatic brain injury – which is what led Ethell to pursue the current research.

In the lab, the researchers artificially increased levels of ephrin-B1 in mice and then tested them for memory retention. They found that the mice could not remember a behavior they had just learned.

In cell culture studies, they added neurons to astrocytes that overexpressed ephrin-B1 and were able to see synapse removal, with the astrocytes “eating up” the synapses.

“Excessive loss of synapses is a problem. The hippocampus, the region of the brain associated primarily with memory, is plastic. Here, new neuronal connections are formed when we learn something new. But the hippocampus has a limited capacity; some connections need to go to ‘make space’ for new connections—new memories. To learn, we must first forget,"

Ethell said.

Keeping A Balance

In contrast to an ephrin-B1 increase, when this protein decreases (or is down-regulated) it results in more synapses — and better learning. The astrocytes, in this case, are not able to attach to the synapses.

“But you don’t want to remember everything. It’s all about maintaining a balance: being able to learn but also to forget,"

said co-first author Amanda Q Nguyen, a Neuroscience Graduate Program student working in Ethell’s lab.

Advice the researchers have for the public is simple: keep the brain — that is, the neurons — active.

“Reading and solving puzzles is a good start,”

Ethell said.

Next, the researchers will work on understanding why some astrocytes remove synapses but other astrocytes do not. They also plan to study the role that inhibitory neurons play in the brain to keep it running smoothly.

Jordan Koeppen, Amanda Q Nguyen, Angeliki M. Nikolakopoulou, Michael Garcia, Sandy Hanna, Simone Woodruff, Zoe Figueroa, Andre Obenaus, Iryna M Ethell Functional consequences of synapse remodeling following astrocyte-specific regulation of ephrin-B1 in the adult hippocampus Journal of Neuroscience 23 May 2018, 3618-17; DOI: 10.1523/JNEUROSCI.3618-17.2018

Image: Ethell lab, UC Riverside

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