Coordinated changes in gene expression activity in neurons and astrocytes in the brains of people with schizophrenia and the elderly point to a possible common biological basis for the cognitive decline seen in both conditions. These findings are reported in a new Nature paper titled, “A concerted neuron-astrocyte program declines in aging and schizophrenia” published by scientists at the Broad Institute, Harvard Medical School, and elsewhere.
The so-called Synaptic Neuron and Astrocyte Program (SNAP), where synapses and neurons adjust their expression in a coordinated way, is observed in healthy brain tissue. The evidence suggests that reduced SNAP activity appears to play a role in aging and schizophrenia, making it a possible target for therapies and interventions for treating cognitive impairment in schizophrenia or at preserving cognitive capabilities in people as they get older.
“Science often focuses on what genes each cell type expresses on its own,” said Steve McCarroll, PhD, director of genomic neurobiology at the Broad’s center for psychiatric research and a senior author on the study. “But brain tissue from many people, and machine-learning analyses of those data, helped us recognize a larger system. These cell types are not acting as independent entities, but have really close coordination.”
Specifically, analysis of postmortem brain tissue from 191 donors aged 22–97 years revealed that both astrocytes and neurons lowered their expression of genes that support synapses in the elderly and people with schizophrenia in a synchronized way. Specifically, when neurons decreased their expression of synapse-related genes, astrocytes likewise changed the expression of their genes that support synapses. “The strength of those relationships took our breath away,” McCarroll noted.
For this study, the scientists used single-nucleus RNA sequencing to analyze gene expression in brain cells from 94 people with schizophrenia and 97 people without the condition. They also developed a computational tool to recognize and capture repeated multicellular gene expression patterns in the data. The SNAP genes that showed changes in expression levels included many that were previously associated with increased risk for schizophrenia.
It’s an added layer of information about the genetic factors involved in schizophrenia. “Science has long known that neurons and synapses are important in risk for schizophrenia,” said Emi Ling, PhD, a postdoctoral researcher in the McCarroll lab and first author on the study. “[B]ut by framing the question a different way—asking what genes each cell type regulates dynamically—we found that astrocytes too are likely involved.”
SNAP expression levels also varied in the healthy people but much of this variation was explained by age—gene expression declined substantially in many, but not all, older individuals. It was true whether they had been diagnosed with schizophrenia or not, suggesting that the SNAP expression changes also affect cognitive abilities as people age.
For their immediate next steps, the scientists are exploring whether SNAP expression changes are present in other cognitive disorders such as bipolar disorder and depression. They also hope to study how SNAP expression impacts learning and cognitive flexibility.