Microglia, the predominant immune cells within the brain, engulf and remodel the extracellular matrix surrounding dendrites in the hippocampus, promoting synapseplasticity and the precise consolidation of long-term memories.

Photo credit: Phi Nguyen, Lynsey Hamilton/UCSF

Date: 6 July 2020

Institution: University of California San Francisco

Study published in: Cell

Digest: Researchers have shown how brain immune (microglia) cells help out neurons form new connections with other neuronal cells by clearing the proteins that come in the way. Earlier it was thought that microglia only helps in engulfing the existing connections.

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.

“The extracellular matrix has been here the whole time,” said the study’s first author Phi Nguyen, a biomedical sciences graduate student at UCSF. “But it’s definitely been understudied.”

Nguyen and his adviser, Anna Molofsky, MD, PhD, an associate professor in the UCSF Department of Psychiatry and Behavioral Sciences, first realized the ECM was important to their research on the hippocampus, a brain structure critical for learning and memory, when an experiment yielded unexpected results. 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,” Molofsky said. “They’re eating the space around synapses – removing obstructions to help new synapses to form.”

The study could be important for understanding – and perhaps one day treating – the kinds of memory problems we see in age related diseases like Alzheimer’s, according to study co-author Mazen Kheirbek, PhD, an associate professor of psychiatry whose lab studies brain circuits involved in mood and emotion.

Molofsky’s lab is now working to identify new, poorly characterized pieces of the matrix to look for as yet undocumented ways it interacts with neurons and microglia in the brain.

“I’m in love with the extracellular matrix,”

Anna Molofsk

 “A lot of people don’t realize that the brain is made up not just of nerve cells, but also cells that keep the brain healthy, and even the space in between cells is packed with fascinating interactions. I think a lot of new treatments for brain disorders can come from remembering that.”

Authors: Anna Molofsky is the senior and corresponding author on the study, and Phi Nguyen is the study’s lead author. Other authors were Leah Dorman, Simon Pan, Ilia Vainchtein, Rafael Han, Hiromi Nakao-Inoue, Sunrae Taloma, Jerika Barron, Ari Molofsky, and Mazen Kheirbek, all at UCSF.

Funding: The research was supported by the Pew Charitable Trusts, the National Institute of Mental Health (R01MH119349, DP2MH116507, R01 MH108623, R01 MH111754, R01 MH117961), the National Science Foundation (graduate research fellowship #1650113), the Burroughs Wellcome Fund, a Weill Scholar Award, the Esther A. and Joseph Klingenstein Fund, and a One Mind Rising Star Award.

Original written by: Lindzi Wessel

Story source: University of California San Francisco

Interested in original study: read here

Article maybe edited for length