Ageing and Schizophrenia could have a shared biological basis

The study published in the Journal Nature, revealed that in individuals with schizophrenia and in older adults without schizophrenia, two brain cell types called astrocytes and neurons reduced their expression of genes that support the junctions between neurons called synapses, compared to healthy or younger people.

Schizophrenia is a challenging mental disorder marked by symptoms like hallucinations, delusions, and cognitive decline. Treatment involves medication, therapy, and support services, but managing the disorder can still be complex due to its multifaceted nature and limited treatment options for cognitive decline.

The team analysed gene expression in more than a million individual cells from postmortem brain tissue from 191 people and discovered tightly synchronised gene expression changes in the two cell types: when neurons decreased the expression of certain genes related to synapses, astrocytes similarly changed the expression of a distinct set of genes that support synapses. The team called this coordinated set of changes the Synaptic Neuron and Astrocyte Program (SNAP). Even in healthy, young people, the expression of the SNAP genes always increased or decreased in a coordinated way in their neurons and astrocytes.

"Science often focuses on what genes each cell type expresses on its own," said Steve McCarroll, a co-senior author on the study and an institute member at the Broad Institute. "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. The strength of those relationships took our breath away."

The findings revealed 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, 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.” concluded McCarroll.

Reference: Emi Ling, 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 Morris, Daniel Meyer, Alyssa Lutservitz, Christopher D. Mullally, Alec Wysoker, Liv Spina, Anna Neumann, Marina Hogan, Kiku Ichihara, Sabina Berretta, Steven A. McCarroll. A concerted neuron–astrocyte program declines in ageing and schizophrenia. Journal: Nature, 2024; DOI: 10.1038/s41586-024-07109-5