microglia의 새로운 역할 발견 (promoting synapse plasticity)

To make new memories, our brain cells first must find one another. Small protrusions that bud out from the ends of neurons' long, branching tentacles dock neurons together so they can talk. These ports of cellular chatter—called synapses, and found in the trillions throughout the brain—allow us to represent new knowledge. But scientists are still learning just how these connections form in response to new experiences and information. Now, a study by scientists in UC San Francisco's Weill Institute for Neurosciences has identified a surprising new way that the brain's immune cells help out.

In recent years, scientists have discovered that the brain's dedicated immune cells, called microglia, can help get rid of unnecessary connections between neurons, perhaps by engulfing synapses and breaking them down. But the new study, published July 1, 2020 in Cell, finds microglia can also do the opposite—making way for new synapses to form by chomping away at the dense web of proteins between cells, clearing a space so neurons can find one another. Continuing to study this new role for microglia might eventually lead to new therapeutic targets in certain memory disorders, the researchers say.

Neurons live within a gelatinous mesh of proteins and other molecules that help to maintain the three-dimensional structure of the brain. This scaffolding, collectively called the extracellular matrix (ECM), has long been an afterthought in neuroscience. For decades, researchers focused on neurons, and, more recently, the cells that support them, have largely considered the ECM unimportant.

But neurobiologists are starting to realize that the ECM, which makes up about 20 percent of the brain, actually plays a role in important processes like learning and memory. At a certain point in brain development, for example, the solidifying ECM seems to put the brakes on the rapid pace at which new neuronal connections turn over in babies, seemingly shifting the brain's priority from the breakneck adaptation to the new world around it, to a more stable maintenance of knowledge over time. Scientists also wonder if a stiffening of the extracellular matrix later in life might somehow correspond to the memory challenges that come with aging.

Knowing that microglia chew away at obsolete synapses, they expected that disrupting microglia function would cause the number of synapses in the hippocampus to shoot up. Instead, synapse numbers dropped. And where they thought they'd find pieces of synapses being broken down in the "bellies" of microglia, instead they found pieces of the ECM. "In this case microglia were eating something different than we expected," 

Before springing into action, the microglia wait for a signal from neurons, an immune molecule called IL-33, indicating that it's time for a new synapse to form,  When researchers used genetic tools to block this signal, microglia failed to fulfill their ECM-chomping duties, leading to fewer new connections between neurons in the brain of mice and leaving mice struggling to remember certain details over time. When researchers instead drove the level of IL-33 signaling up, new synapses increased in number. In older mice, in which brain aging already slows the formation of new connections, ramping up IL-33 helped push the number of new synapses towards a more youthful level.

microglia는 뉴런을 잡아먹는 immune cell만 알려져있었다. 그런데 이 실험을 통해서 microglia는 neuron이 새로 연결되는데에 방해되는, 뉴런들 사이에 있는 ECM을 제거하여 기억형성에 도움을 준다고 한다. IL-33이 trigger가 되어 ECM을 먹는다고 한다. 

 

reference

Phi T. Nguyen et al. Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity, Cell (2020). DOI: 10.1016/j.cell.2020.05.050