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

January 4, 2018 by Dana Smith, University of California, San Francisco
Human astrocytes differentiated from human induced pluripotent stem (iPS) cells. Credit: Zuzana Krejciova

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, it shows that more synapses do not necessarily mean higher intelligence.

Pruning out extraneous synapses to enable existing ones to run more efficiently is just as important as forming new cellular connections. An imbalance between and removal has been linked to psychiatric disorders, including autism and schizophrenia.

UC San Francisco assistant professor Anna Molofsky, MD, Ph.D., is researching how these two processes occur normally during development in the hope of determining how subtle shifts in balance lead to neurodevelopmental disorders. Her research was recently recognized with a prestigious National Institutes of Health New Innovator Award and a Pew Investigator award.

"Most of the psychiatric diseases that we deal with are in some form or another neurodevelopmental, whether it's early childhood experiences that increase your propensity to develop depression and anxiety later in life or whether it's abnormalities in that lead to autism and schizophrenia," explains Molofsky, who is a practicing psychiatrist and trained as a cell and molecular biologist.

The Immune System of the Brain

Instead of focusing on the neurons themselves, Molofsky, a member of the UCSF Weill Institute for Neurosciences, is interested in glial cells, such as astrocytes and microglia, which are commonly thought of as the support cells of the brain. Astrocytes have been shown to play a role in synapse formation, while microglia are implicated in pruning. Glial cells are also instrumental in the brain's immune system, and immune signals communicate with the brain through receptors located on these cells.

The immune system can thus influence brain development by affecting glial cells that control synapse remodeling. As a result, Molofsky says that glial cells and the brain's immune system may be a better target than neurons to intervene during childhood development.

"It's very hard to target neuronal wiring, but it's much easier to target glia, which are fundamentally very plastic ," she says. "In terms of designing treatments, it's important to think about the cell type that's the most malleable, and the immune system is a potential point of intervention."

Immune Proteins and Their Role in Malleability

Molofsky is currently researching the immune signal interleukin 33 (IL-33), which is expressed in astrocytes and correlates with synapse formation. She discovered that as the brain matures, IL-33 expression goes up, thereby enabling more pruning of synapses.

Molofsky first identified IL-33 through a screen to see which genes astrocytes express. Coincidentally, her husband, Ari Molofsky, MD, Ph.D., an assistant professor at UCSF specializing in immunology, studies the same immune signal.

"It's a bit of a natural collaboration because I've been a glial biologist for some time, and are some of the major actors in neuroimmune diseases," she says. The two are now collaborating to study how the immune system communicates with the brain.

Molofsky wonders if treatment with IL-33 or other can make the brain more malleable in adults. Increasing neural plasticity may help with conditions linked to pruning, such as autism and schizophrenia. It may also be beneficial for patients with stroke or where the brain is forced to rewire to cope with the trauma.

"Their brain is incredibly plastic, more plastic than we would think," she says. "Understanding how these developmental mechanisms either exist in adulthood or can be coaxed into working to help the brain to remodel could potentially be beneficial for psychiatric diseases."

Explore further: CD38 gene is identified to be important in postnatal development of the cerebral cortex

Related Stories

CD38 gene is identified to be important in postnatal development of the cerebral cortex

April 7, 2017
The brain consists of neurons and glial cells. The developmental abnormality of glial cells causes various diseases and aberrant cerebral cortex development. CD38 gene knockout is shown to cause aberrant development of glial ...

Star-shaped brain cells orchestrate neural connections

November 8, 2017
Brains are made of more than a tangled net of neurons. Star-like cells called astrocytes diligently fill in the gaps between neural nets, each wrapping itself around thousands of neuronal connections called synapses. This ...

Drugs that alter inhibitory targets offer therapeutic strategies for autism, schizophrenia

February 21, 2017
Memories are formed at structures in the brain known as dendritic spines, which communicate with other brain cells through "synapses." The number of these brain connections decreases by half after puberty in a process termed ...

Breakthrough in understanding of brain development: Immune cell involvement revealed

August 25, 2016
Microglia are cells that combat various brain diseases and injuries by swallowing foreign or disruptive objects and releasing molecules that activate repair mechanisms. Recent findings have suggested these brain cells are ...

Overlooked cells hold keys to brain organization and disease

April 28, 2014
Scientists studying brain diseases may need to look beyond nerve cells and start paying attention to the star-shaped cells known as "astrocytes," because they play specialized roles in the development and maintenance of nerve ...

Study implicates glial cells in fragile X syndrome

October 4, 2016
Research on fragile X syndrome, the most common inherited cause of mental retardation, has focused mostly on how the genetic defect alters the functioning of neurons in the brain. A new study focusing on a different type ...

Recommended for you

Research reveals atomic-level changes in ALS-linked protein

January 18, 2018
For the first time, researchers have described atom-by-atom changes in a family of proteins linked to amyotrophic lateral sclerosis (ALS), a group of brain disorders known as frontotemporal dementia and degenerative diseases ...

Fragile X finding shows normal neurons that interact poorly

January 18, 2018
Neurons in mice afflicted with the genetic defect that causes Fragile X syndrome (FXS) appear similar to those in healthy mice, but these neurons fail to interact normally, resulting in the long-known cognitive impairments, ...

How your brain remembers what you had for dinner last night

January 17, 2018
Confirming earlier computational models, researchers at University of California San Diego and UC San Diego School of Medicine, with colleagues in Arizona and Louisiana, report that episodic memories are encoded in the hippocampus ...

Recording a thought's fleeting trip through the brain

January 17, 2018
University of California, Berkeley neuroscientists have tracked the progress of a thought through the brain, showing clearly how the prefrontal cortex at the front of the brain coordinates activity to help us act in response ...

Midbrain 'start neurons' control whether we walk or run

January 17, 2018
Locomotion comprises the most fundamental movements we perform. It is a complex sequence from initiating the first step, to stopping when we reach our goal. At the same time, locomotion is executed at different speeds to ...

Neuroscientists suggest a model for how we gain volitional control of what we hold in our minds

January 16, 2018
Working memory is a sort of "mental sketchpad" that allows you to accomplish everyday tasks such as calling in your hungry family's takeout order and finding the bathroom you were just told "will be the third door on the ...

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.