Synapse 'protection' signal found; helps to refine brain circuits

October 10, 2018, Children's Hospital Boston
Credit: CC0 Public Domain

The developing brain is constantly forming new connections, or synapses, between nerve cells. Many connections are eventually lost, while others are strengthened. In 2012, Beth Stevens, Ph.D. and her lab at Boston Children's Hospital showed that microglia, immune cells that live in the brain, prune back unwanted synapses by engulfing or "eating" them. They also identified a set of "eat me" signals required to promote this process: complement proteins, best known for helping the immune system combat infection.

In new work published in Neuron, Stevens and colleagues reveal the flip side: a "don't eat me" signal that prevents from pruning useful connections away. The signal, a protein called CD47, communicates with a receptor on microglia called SIRP alpha.

"We think this is first evidence of a protective cue that microglia can read out that tells them not to prune," says Stevens. "Our findings demonstrate that synaptic protection is necessary to ensure normal development."

The neuro-immune connection

Like complement, CD47 also plays a role in the immune system, where it is part of a group of "don't eat me" signals that prevent damage or removal of healthy cells in situations of infection or challenge by pathogens. (In fact, some cancer immunotherapies work by inhibiting CD47, encouraging the immune system to attack cancer cells.)

"We asked, are any of these molecules expressed in the brain?" says Stevens. "Sure enough, CD47 is expressed very highly and is found throughout the brain. We think that, as seen following an immune challenge, the brain is using it as a protective cue, telling microglia not to prune specific synapse. The brain and the immune system are sharing signals in a way that we're only beginning to appreciate."

CD47: the 'yin' to complement's 'yang'?

To model synapse development and pruning in the brain, Stevens and colleagues tapped a time-tested model of synapse refinement: the developing visual system.

They found that during the time when synapse pruning in the visual system is at its peak, CD47 is enriched in the developing visual thalamus and localized to synapses. They also found that mice lacking CD47 (through a genetic deletion) had increased pruning activity by microglia and fewer synapses than normal mice, having lost the "don't eat me" signal.

The findings add fuel to the idea that the brain has a balance of opposing factors that help fine-tune its connections—a yin/yang of sorts.

"The study is exciting because it suggests a possible cooperative interaction between 'eat me' and 'don't eat me' signals that instruct microglia what to do when they see a synapse," says Stevens. "As we start to delve deeper and identify new molecules and mechanisms by which microglia are pruning, it's important to think how all these things fit together. It's not one pathway, but a coordinated effort."

A molecule to regulate activity-dependent eating

Another important aspect of the work is the link between CD47 and the activity of , or . Pioneering work over many decades has shown that the activity of neurons regulates the pruning process, but much less is known about how this happens on a molecular level.

Previous work in the Stevens lab showed that microglia, when given the choice, preferentially eat synapses from less active neurons compared to more active neurons. However, how microglia can tell these synapses apart remained unknown. The new study finds that in response to changes in neuronal activity, CD47 localization changes—with CD47 preferentially localized to synapses from the more active neurons. In the absence of CD47, microglia appear unable to distinguish different activity levels, as they no longer prefer to eat from less active neurons.

"We think this is the first example of a molecule regulated by neuronal activity that can put the brakes on microglial engulfment," says Stevens. "Exploring the mechanisms underlying this and determining whether it applies more generally to synaptic refinement in other brain regions will be an important aspect of future study."

Preventing pruning?

Though it's still too soon to say, the study could have also implications for understanding and treating brain disorders. A number of neurodegenerative diseases such as Alzheimer's disease and schizophrenia involve synapse loss, possibly through aberrant activation of pruning.

"Whether we can leverage this protective 'don't eat me' signal to curb pathological synapse loss in disease is an open question," says Daniel Wilton, Ph.D., second author on the Neuron paper.

Emily Lehman, now at Clark + Elbing LLP, is the paper's first author.

Explore further: Microglia pruning brain synapses captured on film for the first time

Related Stories

Microglia pruning brain synapses captured on film for the first time

March 26, 2018
For the first time, EMBL researchers have captured microglia pruning synaptic connections between brain cells. Their findings show that the special glial cells help synapses grow and rearrange, demonstrating the essential ...

Study shows how immune cells change wiring of the developing mouse brain

May 23, 2012
Researchers have shown in mice how immune cells in the brain target and remove unused connections between brain cells during normal development. This research, supported by the National Institutes of Health, sheds light on ...

Researchers identify brain cells responsible for removing damaged neurons after injury

June 25, 2018
Researchers at the University of Virginia School of Medicine have discovered that microglia, specialized immune cells in the brain, play a key role in clearing dead material after brain injury. The study, which will be published ...

Immune cells destroy healthy brain connections, diminish cognitive function in obese mice

September 10, 2018
Obesity leads to cognitive impairment by activating microglial cells, which consume otherwise functional synapses in the hippocampus, according to a study of male mice published in JNeurosci. The research suggests that microglia ...

Brain's immune system may be key to better treatments for psychiatric disorders

January 4, 2018
Between the ages of two and four, the human brain has an estimated one quadrillion synapses – the electrical connections between neurons. That is the highest it will ever have, but as the world is not run by 3-year-olds, ...

Study points to immune system's role in neural development

February 2, 2018
Between the ages of two and four, the human brain has an estimated one quadrillion synapses – the electrical connections between neurons. As we age, pruning out extraneous synapses enables existing ones to run more efficiently ...

Recommended for you

Research shows signalling mechanism in the brain shapes social aggression

October 19, 2018
Duke-NUS researchers have discovered that a growth factor protein, called brain-derived neurotrophic factor (BDNF), and its receptor, tropomyosin receptor kinase B (TrkB) affects social dominance in mice. The research has ...

Good spatial memory? You're likely to be good at identifying smells too

October 19, 2018
People who have better spatial memory are also better at identifying odors, according to a study published this week in Nature Communications. The study builds on a recent theory that the main reason that a sense of smell ...

How clutch molecules enable neuron migration

October 19, 2018
The brain can discriminate over 1 trillion odors. Once entering the nose, odor-related molecules activate olfactory neurons. Neuron signals first accumulate at the olfactory bulb before being passed on to activate the appropriate ...

Scientists discover the region of the brain that registers excitement over a preferred food option

October 19, 2018
At holiday buffets and potlucks, people make quick calculations about which dishes to try and how much to take of each. Johns Hopkins University neuroscientists have found a brain region that appears to be strongly connected ...

Gene plays critical role in noise-induced deafness

October 19, 2018
In experiments using mice, a team of UC San Francisco researchers has discovered a gene that plays an essential role in noise-induced deafness. Remarkably, by administering an experimental chemical—identified in a separate ...

Brain cells called astrocytes have unexpected role in brain 'plasticity'

October 18, 2018
When we're born, our brains have a great deal of flexibility. Having this flexibility to grow and change gives the immature brain the ability to adapt to new experiences and organize its interconnecting web of neural circuits. ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.