Summary: Researchers have identified a coordinated set of cellular and molecular changes in the brains of people with schizophrenia and in older adults that point to a shared biological basis for cognitive decline. The findings reveal how neurons and astrocytes act together to support synaptic function and how disruption of that partnership may contribute to impaired cognition in both conditions.
In an analysis of gene expression across more than a million individual brain cells from 191 donors, scientists discovered a synchronized reduction in genes that help form and maintain synapses—the communication junctions between neurons. This coordinated program, named the Synaptic Neuron and Astrocyte Program (SNAP), involves complementary changes in neurons and astrocytes and appears to decline with age and in schizophrenia, offering new insight into mechanisms that underlie cognitive changes.
The identification of SNAP improves our understanding of synaptic dynamics in the human cortex and points toward possible strategies to preserve or restore cognitive function.
Key Facts:
- Shared biological signature: Similar gene expression shifts in astrocytes and neurons were observed in both schizophrenia and normal aging, suggesting overlapping mechanisms behind cognitive decline.
- The SNAP program: The Synaptic Neuron and Astrocyte Program (SNAP) is a coordinated gene expression pattern in neurons and astrocytes that reflects synaptic health and contributes to cognitive variability; its activity tends to decrease with age.
- Therapeutic potential: Understanding SNAP’s regulation may reveal lifestyle factors or drug targets that could support synaptic maintenance and help treat cognitive impairments linked to schizophrenia and aging.
Source: Broad Institute
Researchers from the Broad Institute of MIT and Harvard, Harvard Medical School, and McLean Hospital have reported nearly identical suites of gene-activity changes in cortical brain tissue from people with schizophrenia and from older adults.
Those parallel changes point to a shared biological foundation for the cognitive difficulties commonly seen in schizophrenia and in advanced age.
Published in Nature, the study used single-nucleus RNA sequencing to measure gene expression in more than 1.2 million individual cells taken from postmortem prefrontal cortex samples of 191 donors.
The team found that, compared with younger or unaffected individuals, both people with schizophrenia and older adults showed lower expression of genes that support synapses in two critical cell types: excitatory and inhibitory neurons and cortical astrocytes. Importantly, the changes in neurons and astrocytes were tightly synchronized: when neurons reduced expression of synapse-related genes, astrocytes altered expression of a complementary set of synaptic-support genes.
The investigators named this coordinated pattern the Synaptic Neuron and Astrocyte Program (SNAP). Even among healthy young individuals, SNAP genes varied in a coordinated way across neurons and astrocytes, indicating a deeply linked system rather than independent cellular responses.
“Research often examines gene expression within each cell type in isolation,” said Steve McCarroll, co-senior author and Broad Institute member. “Analyzing many samples together with machine-learning approaches revealed a larger, tightly coordinated system. The strength of these relationships was striking.”
While schizophrenia is often recognized for psychotic symptoms such as hallucinations and delusions—symptoms that can be managed with medication—it also causes cognitive decline that lacks effective treatments and mirrors declines seen in aging. These new results suggest that similar cellular and molecular alterations may underlie cognitive impairment across both conditions.
“To reveal coordinated changes between astrocytes and neurons in schizophrenia and aging, we needed tissue from a very large number of donors,” said Sabina Berretta, co-senior author and associate professor at Harvard Medical School. The authors express their gratitude to the donors and their families for enabling this research.
McCarroll directs genomic neurobiology at the Broad’s Stanley Center for Psychiatric Research and is a professor at Harvard Medical School. Berretta leads the Harvard Brain Tissue Resource Center, which provided tissue samples. Emi Ling, a postdoctoral researcher in McCarroll’s lab, is the paper’s first author.
SNAP insights
Neuronal communication depends on synapses, where neurons exchange signals. The brain continually forms new synapses and removes others—a process linked to learning, flexibility, and plasticity. Prior work has connected many schizophrenia-risk genes to synaptic function, and the new study adds a coordinated astrocyte contribution to that picture.
Using single-nucleus RNA sequencing to capture cell-level gene expression, the team analyzed samples from 94 donors with schizophrenia and 97 without. They found that when neurons increased expression of genes encoding synaptic components, astrocytes concurrently increased expression of distinct synaptic-support genes, including genes for cholesterol synthesis that astrocytes supply to synaptic membranes.
The SNAP set contains multiple genes previously linked to schizophrenia, and analyses indicate that both neuronal and astrocytic SNAP components contribute to genetic vulnerability for the disorder. “By asking how genes are dynamically regulated across cell types, we found that astrocytes are likely involved in risk for schizophrenia as well as neurons,” said Ling.
SNAP expression also varied substantially among people without schizophrenia, implying a role in normal cognitive differences. Much of this variation correlated with age: in many—but not all—older individuals SNAP expression declined, whether or not they had schizophrenia.
McCarroll and colleagues hope that understanding SNAP may reveal life factors or therapies that support SNAP activity, potentially preserving cognitive flexibility in aging and treating cognitive deficits in schizophrenia. Ongoing work is investigating whether SNAP-related changes occur in other psychiatric conditions such as bipolar disorder and depression, how SNAP appears across different brain regions, and how it influences learning and adaptability.
Funding: This research was supported by the Stanley Family Foundation, the Simons Collaboration on Plasticity and the Aging Brain, the National Institute of Mental Health, and the National Human Genome Research Institute at the National Institutes of Health.
About this aging and schizophrenia research news
Author: Allessandra DiCorato
Source: Broad Institute
Contact: Allessandra DiCorato – Broad Institute
Image: Image credited to Neuroscience News
Original Research: Open access. “Concerted neuron-astrocyte program declines in ageing and schizophrenia” by Steve McCarroll et al., Nature. DOI: 10.1038/s41586-024-07109-5
Abstract
Concerted neuron-astrocyte program declines in ageing and schizophrenia
Human cortical biology varies among individuals and across the lifespan, but these differences are not yet fully explained at the cellular level. Using single-nucleus RNA sequencing of prefrontal cortex samples from 191 donors aged 22–97 years, including people with schizophrenia and healthy controls, latent-factor analysis revealed a relationship between neuronal and astrocytic gene expression.
When cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes concurrently expressed distinct genes with synaptic functions and genes for cholesterol synthesis—an astrocyte-supplied component of synaptic membranes. The authors term this coordinated relationship the Synaptic Neuron and Astrocyte Program (SNAP).
In both schizophrenia and aging—conditions associated with reduced cognitive flexibility and plasticity—cells showed reduced SNAP expression: astrocytes, glutamatergic neurons, and GABAergic neurons all exhibited coordinated declines. The astrocytic and neuronal elements of SNAP were enriched for genes that carry genetic risk for schizophrenia. Because SNAP varies quantitatively even among similarly aged healthy individuals, it may underlie aspects of normal interindividual cognitive differences and represent a convergence point for multiple pathophysiological processes.