In This Article
- In this study, investigators created a new system that makes it possible to examine synaptic pruning in a patient-derived stem cell model
- They demonstrated abnormal increases in pruning in models from individuals with schizophrenia compared to those from healthy controls
- This increased pruning could be blocked by minocycline, an FDA-approved antibiotic suggested to have an anti-inflammatory effect
- Using electronic health records, the investigators found a reduction in rates of schizophrenia among individuals who received minocycline treatment for acne, compared to those who received other treatments
Researchers, led by Roy Perlis, MD, MSc, director of the Center for Quantitative Health at Massachusetts General Hospital, have created the first human cellular model of synaptic pruning in schizophrenia. This model not only sheds light on the process by which schizophrenia develops in humans, but also is being used to investigate new therapies for the disease.
"As a psychiatrist, I do this work because our existing therapeutics are inadequate," says Dr. Perlis. "Part of the excitement for me is having a cellular model that can be applied to find new interventions."
The Role of Synaptic Pruning in Brain Development
Synaptic pruning is a critical process in brain development. "The brain initially develops a large number of connections," says Dr. Perlis. "Then there's a process of trimming and modifying connections as part of normal development."
Synaptic pruning occurs throughout the lifespan, but is particularly active in some regions during adolescence, which is also typically when schizophrenia first manifests.
Previous studies have hypothesized a possible connection between excessive synaptic pruning and schizophrenia, and evidence of this link exists in postmortem brain studies and research involving human genetics. Researchers have suspected that C4A, a risk gene for schizophrenia, is relevant in pruning, but they could not show human cellular evidence of this relationship.
"Mouse models are valuable in many contexts, but here we knew we needed a human model," says Dr. Perlis.
Creating Microglia and Neurons from Human Cells
Dr. Perlis' team took blood cells from people with and without schizophrenia and modified them to behave like microglia, which are active in synaptic pruning. Because neurons are fragile and laborious to grow in the volume needed for research, the team also engineered clusters of fluorescent-labeled synaptosomes from people with and without schizophrenia, which they combined with the microglia.
The investigators then compared the synaptic pruning in the patients with schizophrenia to healthy controls. They found excessive pruning in synapses derived from men with schizophrenia, compared to in the cells derived from controls.
"It is among the first illustrations in human cells of the mechanism by which one of the schizophrenia risk genes may be acting," Dr. Perlis says. "What our models show is that the amount of C4A expression is related to the amount of phagocytosis we observe. Importantly, though, C4A only explains a small amount of the effects in our models, suggesting there is much more to the story."
Using Electronic Health Records to Investigate Schizophrenia Prevention
These findings are an important milestone in shifting the focus from symptomatic treatment to prevention in psychiatric illnesses. Confirming abnormal synaptic pruning in schizophrenia allowed Dr. Perlis' team to take the next step and look for new therapeutics.
The antibiotic drug minocycline, which is commonly prescribed to treat acne, is known to have anti-inflammatory properties. Scientists have hypothesized that inflammation worsens neurodegeneration, so minocycline has been studied in psychiatric illnesses, including as an acute treatment for schizophrenia. Until now, no one had ever investigated the drug for schizophrenia prevention.
As part of this study, Dr. Perlis' team treated microglial cell cultures with minocycline before adding them to patient-derived cellular models. As they increased the minocycline dose, phagocytosis decreased to the point where they could completely block the process.
To further explore minocycline's potential to decrease schizophrenia risk, they then harnessed the power of electronic health record data and analyzed 10 years worth of electronic health records for more than 22,000 people.
The team looked at people treated with minocycline and other antibiotics between the ages of 10 and 18 and found the rates of developing schizophrenia were ~60% lower among people who had been treated with minocycline for at least three months.
"The combination of electronic health records and cellular models can be powerful because they are intersecting lines of evidence that help us think about potential interventions," Dr. Perlis says. "It's a powerful way to understand what drugs are doing at a cellular level and what they're doing at a population level."
Shifting From Symptomatic Treatment to Prevention
Dr. Perlis emphasizes the results of this study represent a first step only. "There are many parts of the story that need to be clarified. How well will minocycline get into the brain? How well will it be tolerated? What's the right dose? Can we discover better options? We are laying the groundwork for what we hope will be prevention studies going forward," says Dr. Perlis.
Dr. Perlis notes that while other areas of medicine are already focused on disease modification, it's time for psychiatry to catch up.
"In rheumatoid arthritis, the idea is we're not just going to control your pain—we're actually going to try to block the disease process so your joint disease doesn't get worse," he says. "We would like to find disease modifiers in psychiatry. As someone who has been working in genetics for 20 years, it's nice to see the genetics mature to the point that we can start to do that."
Learn more about the Center for Quantitative Health
Learn more about schizphrenia research at Mass General