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Developing brains continuously sprout new neuronal connections called synapses as they understand and remember. Important connections — the ones that are repeatedly introduced, such as how to avoid danger — are nurtured and reinforced, while links deemed unnecessary are pruned away.
Adult brains experience similar pruning, but it was unclear why or how synapses in the adult brain get removed.
Now, a group of KAIST researchers has discovered the mechanism inherent plasticity and, potentially, neurological disorders in mature brains. They released their findings on December 23 in Nature.
Gray matter in the mind contains microglia and astrocytes, two complementary cells that, among other things, encourage neurons and synapses. Microglial are a frontline immunity defense, in charge of eating pathogens and dead cells, and astrocytes are star-shaped cells which help structure the mind and maintain homeostasis by helping to control signaling between neurons.
Our findings have profound implications for our understanding of how neural circuits change during learning and memory, as well as in diseases. Changes in synapse number have a strong association with the prevalence of various neurological disorders, such as autism spectrum disorder, schizophrenia, frontotemporal dementia, and several forms of seizures.”
Won-Suk Chung, Paper Author and Assistant Professor, Department of Biological Sciences, KAIST (Korea Advanced Institute of Science and Technology)
According to Professor Chung, it is generally thought that microglial eat synapses as part of its clean-up effort in a process known as phagocytosis.
“Using novel tools, we show that, for the first time, it’s astrocytes and not microglia that constantly eliminate unnecessary and excessive adult excitatory synaptic connections in response to neuronal activity,” Professor Chung said. “Our paper challenges the general consensus in this field that microglia are the principal synapse phagocytes that control synapse numbers in the brain.”
Professor Chung and his group developed a molecular sensor to detect synapse elimination by glial cells and measured how frequently and by which kind of cell synapses were eliminated.
They also deployed it in a mouse model without MEGF10, the gene which enables astrocytes to eliminate synapses. Adult animals with this defective astrocytic phagocytosis had unusually increased excitatory synapse numbers in the hippocampus.
Through a collaboration with Dr. Hyungju Park at KBRI, they showed that these increased excitatory synapses are functionally impaired, which induces defective learning and memory formation in MEGF10 deleted animals.
“During this procedure, we show that, at least in the adult hippocampal CA1 area, astrocytes are the major player in removing synapses, and this astrocytic function is essential for controlling synapse number and plasticity,” Chung said.
Professor Chung noted that researchers are only beginning to understand how synapse elimination affects maturation and homeostasis in the brain. In his group’s preliminary statistics in other brain regions, it seems that each region has different rates of synaptic removal by astrocytes.
They suspect a variety of external and internal factors are influencing how astrocytes modulate each regional circuit and plan to elucidate these variables.
“Our long-term objective is understanding how astrocyte-mediated synapse turnover affects the initiation and development of various neurological disorders,” Professor Chung said. “It’s intriguing to postulate that modulating astrocytic phagocytosis to restore synaptic connectivity might be a novel strategy in treating various brain disorders.”
KAIST (Korea Advanced Institute of Science and Technology)
Lee, J-H., et al. (2020) Astrocytes phagocytose adult hippocampal synapses for circuit homeostasis. Nature. doi.org/10.1038/s41586-020-03060-3.