At a glance:
- Study finds people with schizophrenia and older adults have strikingly similar sets of changes in gene activity in two types of brain cells.
- Findings suggest a shared biological basis for cognitive impairment in schizophrenia and aging and point to new strategies for treating it.
- The work also implicates a cell type not previously known to affect genetic vulnerability for schizophrenia.
Brain tissue samples from people with schizophrenia and from older adults have strikingly similar sets of changes in gene activity in two types of brain cells, suggesting a common biological basis for the cognitive impairment often seen in people with schizophrenia and in older people, according to new research.
The findings — published March 6 in Nature and led by researchers at Harvard Medical School, the Broad Institute of MIT and Harvard, and McLean Hospital — point to new strategies for treating cognitive impairment.
The work also implicates a cell type not previously known to affect genetic vulnerability for schizophrenia.
The discoveries arose from training an artificial intelligence model to analyze gene activity across many kinds of cells in brain tissue samples from nearly 200 people.
“Science often focuses on what genes each cell type expresses on its own,” said co-senior author Steve McCarroll, the Dorothy and Milton Flier Professor of Biomedical Science and Genetics in the Blavatnik Institute at HMS and director of genomic neurobiology for the Stanley Center for Psychiatric Research at the Broad Institute.
“But brain tissue from many people, and machine-learning analyses of those data, helped us recognize a larger system,” he said.
An unexpected cell relationship
The researchers analyzed patterns of gene activity, known as gene expression, in more than 1 million cells from postmortem brain tissue from 191 people.
They found that in individuals with schizophrenia and in older adults without schizophrenia, two brain cell types — astrocytes and neurons — had lower activity of genes that support the junctions between neurons, called synapses, compared to healthy or younger people.
The team also discovered tightly synchronized changes in gene expression in the two cell types. When neurons lowered the expression of certain genes related to synapses, astrocytes did too.
The team called this coordinated set of changes the Synaptic Neuron and Astrocyte Program, or SNAP.
They found that even in healthy young people, the expression of SNAP genes always increased or decreased in a coordinated way in neurons and astrocytes.
“These cell types are not acting as independent entities but have really close coordination,” said McCarroll. “The strength of those relationships took our breath away.”
Shared roots
Schizophrenia is well known for causing hallucinations and delusions, which can be at least partly treated with medications. But it also causes debilitating cognitive decline, which has no effective treatments.
Cognitive decline is common in aging as well.
The new findings suggest that the cognitive changes in both conditions might involve similar cellular and molecular alterations in the brain.
The strength of those relationships took our breath away.
Steve McCarroll
The brain works in large part because neurons connect with other neurons at synapses, where they pass signals to one another. The brain constantly forms new synapses and prunes old ones. Scientists think new synapses help our brains stay flexible, and studies — including previous efforts by scientists in McCarroll’s lab and international consortia — have shown that many genetic factors linked to schizophrenia involve genes that contribute to synapse function.
In the new study, McCarroll, co-senior author Sabina Berretta, and colleagues used single-nucleus RNA sequencing, which measures gene expression in individual cells, to better understand how the brain naturally varies across individuals.
They analyzed 1.2 million cells from 94 people with schizophrenia and 97 people without.
They found that when neurons boosted expression of genes that encode parts of synapses, astrocytes increased the expression of a distinct set of genes involved in synaptic function.
New insights into schizophrenia risk
These genes, which make up SNAP, included many previously identified risk factors for schizophrenia. But unlike previous work that implicated only neurons in schizophrenia risk, the team’s analyses indicated that both neurons and astrocytes shape genetic vulnerability for the condition.
“Science has long known that neurons and synapses are important in risk for schizophrenia, but by framing the question a different way — asking what genes each cell type regulates dynamically — we found that astrocytes too are likely involved,” said first author Emi Ling, a postdoctoral researcher in the McCarroll lab.
Looking deeper into SNAP
To their surprise, the researchers also found that SNAP varied greatly even among people without schizophrenia, suggesting that SNAP could be involved in cognitive differences in healthy humans.
Much of this variation was explained by age. SNAP declined substantially in many — but not all — older individuals, including both people with and without schizophrenia.
With better understanding of SNAP, McCarroll says he hopes it might be possible to identify life factors that positively influence SNAP and develop medicines that help stimulate SNAP as a way to treat the cognitive impairments of schizophrenia or help people maintain their cognitive flexibility as they age.
In the meantime, McCarroll, Berretta, and their team are working to understand whether these changes are present in other conditions such as bipolar disorder and depression.
They also aim to uncover the extent to which SNAP appears in other brain areas and how SNAP affects learning and cognitive flexibility.
The current work wouldn’t have been possible without tissue samples from a large number of people, said Berretta, HMS associate professor of psychiatry at McLean Hospital and director of the Harvard Brain Tissue Resource Center, which provided tissue for the study.
“Our gratitude goes to all donors who chose to donate their brain to research to help others suffering from brain disorders and to whom we’d like to dedicate this work,” she said.
Authorship, funding, disclosures
McCarroll is also an institute member at the Broad Institute.
Additional authors are James Nemesh, Melissa Goldman, Nolan Kamitaki, Nora Reed, Robert E. Handsaker, Giulio Genovese, Jonathan S. Vogelgsang, Sherif Gerges, Seva Kashin, Sulagna Ghosh, John M. Esposito, Kiely French, Daniel Meyer, Alyssa Lutservitz, Christopher D. Mullally, Alec Wysoker, Liv Spina, Anna Neumann, Marina Hogan, and Kiku Ichihara.
This work was supported by the Stanley Family Foundation, the Simons Collaboration on Plasticity and the Aging Brain, and the National Institute of Mental Health and the National Human Genome Research Institute at the National Institutes of Health (grants U01MH115727, P50MH115874, and T32HG002295).
With reporting from Karen Zusi-Tran.
