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A new study led by researchers at the Karolinska Institutet in Solna, Sweden, in collaboration with scientists from the Allen Institute for Brain Science and others, has pinpointed specific cell types in the brain that may contribute to schizophrenia. That finding will help guide research efforts to uncover new targets for better treatments of the disease, the researchers said.
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The study, which was published this week in the journal Nature Genetics, paired knowledge of the complex genetic background of the disease with detailed datasets of how those genes behave in mouse and human brain cells. Their work identified three types of neurons that are most tightly linked to the disease-driving genes.
Now that they know which cell types are likely responsible for the disease, “researchers can study what might be going wrong in those cells,” said Trygve Bakken, M.D., Ph.D., a researcher at the Allen Institute for Brain Science and one of the study authors.
Schizophrenia is partly a genetic disease – together with the environment, the specific makeup of a person’s genetic code drives the disorder. But the number of genes involved in schizophrenia has proven to be immense. Unlike so-called single gene disorders, where a mutation in one gene is responsible for the disease (think cystic fibrosis or Huntington disease), schizophrenia has been linked to hundreds – or maybe even thousands – of different genes.
Unravelling the contributions of all those genes is no easy task. Previous studies had identified neurons as the broad type of cell driving the disease, Bakken said, but their hope was to drill down further into the disease by pinpointing a more specific class or classes of cells responsible.
“That would make the problem of understanding schizophrenia somewhat more tractable,” Bakken said.
The research team, which was led by Jens-Hjerling-Leffler, Ph.D., and Patrick Sullivan, M.D., of the Karolinska Institutet, asked which cell types in mouse and human brains are actually using the hundreds of genes associated with schizophrenia. To do this, they turned to large datasets of mouse and human brain gene expression that measure the complete sets of genes used in individual cells. Different sets of genes are responsible for the function of different types of cells, and by looking at the activity of genes linked to schizophrenia the researchers could pinpoint which cells would be affected if those genes were disrupted.
The datasets came from the Karolinska Institutet, the Allen Institute for Brain Science and the Broad Institute of MIT and Harvard. This study is an example of the power of studying the brain at the level of its component cell types, said Allen Institute for Brain Science Investigator Ed Lein, Ph.D., also an author on the study.
“The brain is a cellular organ, and diseases that affect the brain ultimately arise from dysfunction of specific types of cells,” Lein said. “Taking this kind of high-resolution approach to studying disease will open up a lot of avenues for new research.”
Comparing information across the datasets, the researchers pulled out the three distinct types of neurons that turn on the schizophrenia-associated genes. The Seattle and Sweden teams are now trying to pin down the affected cell types with even higher specificity.
Although this study doesn’t identify what happens to these many genes in the brain cells of people with schizophrenia, Bakken said it’s a “first small step” toward identifying possible pathways for better schizophrenia treatments by narrowing the field of cell types those drugs may need to target.
The Allen Institute for Brain Science is a division of the Allen Institute, an independent, 501(c)(3) nonprofit medical research organization, and is dedicated to accelerating the understanding of how the human brain works in health and disease. Using a big science approach, the Allen Institute generates useful public resources used by researchers and organizations around the globe, drives technological and analytical advances, and discovers fundamental brain properties through integration of experiments, modeling and theory. Launched in 2003 with a seed contribution from founder and philanthropist, the late Paul G. Allen, the Allen Institute is supported by a diversity of government, foundation and private funds to enable its projects. The Allen Institute for Brain Science’s data and tools are publicly available online at brain-map.org.