Researchers at the Broad Institute of MIT and Harvard, Harvard Medical School, and McLean Hospital have discovered a strikingly similar set of changes in gene activity in the brain tissue of people with schizophrenia and older adults. These changes suggest a common biological basis for the cognitive impairment often seen in people with schizophrenia and the elderly.
In a study published in NatureIn the paper, the team describes how they analyzed gene expression in more than one million individual cells from post-mortem brain tissue from 191 people. They found that in people with schizophrenia and in older adults without schizophrenia, two types of brain cells called astrocytes and neurons reduced the expression of genes that support junctions between neurons called synapses, compared with healthy or younger people. They also discovered closely synchronized changes in gene expression in the two cell types: when neurons decreased the expression of certain genes related to synapses, astrocytes similarly changed the expression of a different set of genes that support synapses.
The team called this coordinated set of changes the Synaptic Neuron and Astrocyte Program (SNAP). Even in young, healthy people, the expression of SNAP genes always increased or decreased coordinately in their neurons and astrocytes.
“Science often focuses on which genes each cell type expresses on its own,” said Steve McCarroll, co-senior author of the study and a member of the Broad Institute. “But brain tissue from many people and analyzes of that data using machine learning helped us recognize a larger system. These types of cells do not act as independent entities, but are very closely coordinated. The strength of those relationships tells us took your breath away.”
Schizophrenia is well known for causing hallucinations and delusions, which can be treated, at least in part, with medications. But it also causes debilitating cognitive decline, which has no effective treatments and is also common in aging. The new findings suggest that cognitive changes in both conditions could involve similar cellular and molecular alterations in the brain.
“To detect coordination between astrocytes and neurons in schizophrenia and aging, we needed to study tissue samples from a large number of individuals,” said Sabina Berretta, co-senior author of the study and associate professor at Harvard Medical School. and Researcher in the field of psychiatric disorders. “Our gratitude goes to all the donors who decided to donate their brain to research and help other people suffering from brain disorders and to whom we would like to dedicate this work.”
McCarroll is also director of genomic neurobiology at the Broad’s Stanley Center for Psychiatric Research and a professor at Harvard Medical School. Berretta also directs the Harvard Brain Tissue Resource Center (HBTRC), which provided tissue for the study. Emi Ling, a postdoctoral researcher in McCarroll’s lab, was the study’s first author.
SNAP Outlook
The brain works largely because neurons connect to other neurons at synapses, where they pass signals to each other. The brain constantly forms new synapses and prunes old ones. Scientists believe that 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 the function of the synapses. synapses.
In the new study, McCarroll, Berretta and their colleagues used single-nucleus RNA sequencing, which measures gene expression in individual cells, to better understand how the brain naturally varies between individuals. They analyzed 1.2 million cells from 94 people with schizophrenia and 97 without it.
They found that when neurons boosted the expression of genes that encode parts of synapses, astrocytes boosted the expression of a different set of genes involved in synaptic function. These genes, which make up the SNAP program, included many previously identified risk factors for schizophrenia. The team’s analyzes indicated that both neurons and astrocytes shape genetic vulnerability to disease.
“Science has long known that neurons and synapses are important in the risk of schizophrenia, but by asking the question in a different way (by asking which genes each cell type dynamically regulates) we found that astrocytes are probably also involved. “Ling said.
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 is explained by age; SNAP decreased substantially in many, but not all, older people, including people with and without schizophrenia.
With a better understanding of SNAP, McCarroll says he hopes it will be possible to identify vital factors that positively influence SNAP and develop medications that help stimulate SNAP, as a way to treat the cognitive impairments of schizophrenia or help people maintain their Cognitive flexibility as you age.
Meanwhile, 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 discover to what extent SNAP appears in other areas of the brain and how SNAP affects learning and cognitive flexibility.
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This work was supported by the Stanley Family Foundation, the Simons Collaboration on Brain Plasticity and Aging, and the National Institute of Mental Health and the National Human Genome Research Institute of the National Institutes of Health.