Unveiling SNAP: Shared Brain Changes in Schizophrenia and Aging

Researchers from the Broad Institute of MIT and Harvard, Harvard Medical School, and McLean Hospital have discovered startlingly comparable Brain Changes in gene activity within brain tissue from individuals with schizophrenia and older adults. These alterations point to a shared biological cause for the cognitive decline frequently observed in elderly and schizophrenic patients.

Exploring Gene Expression in Brain Tissue

The team details how they examined gene expression in over a million individual cells from post-mortem brain tissue of 191 individuals in a study published in Nature. They found that, in comparison to younger or healthy individuals, the expression of genes supporting the synaptic connections between neurons was decreased in both older persons without schizophrenia and those with schizophrenia. These individuals belonged to the astrocyte and neuron cell types of the brain. Additionally, they discovered that the changes in gene expression between these two cell types were closely timed: astrocytes altered the expression of a different group of genes supporting synapses, mirroring the changes in neurons related to synapses.

Introducing the Synaptic Neuron and Astrocyte Program (SNAP) and Brain Changes

The Synaptic Neuron and Astrocyte Program (SNAP) is the name given by the researchers to this coordinated series of modifications. The consistent upregulation or downregulation of SNAP gene expression in neurons and astrocytes was evident even in young, healthy individuals.

“Genes that each cell type expresses on its own are the focus of science a lot of the time,” said co-senior author Steve McCarroll of the Broad Institute. “However, by analyzing data from machine learning evaluations on a vast number of brain tissue samples, we identified a bigger system. These cell types exhibit extremely close collaboration instead of functioning as separate entities. We were astounded by those relationships’ strength.”

Cognitive Deterioration and Brain Changes in Schizophrenia and Aging

Medication can at least partially manage common symptoms of schizophrenia, such as hallucinations and delusions. However, it also results in crippling cognitive deterioration, which is prevalent in aging and currently has no known therapy. According to the new research, there may be comparable chemical and molecular changes in the brain that underlie cognitive deficits in both cases.

“We needed to study tissue samples from a very large number of individuals to detect coordination between astrocytes and neurons in schizophrenia and aging,” stated Sabina Berretta, an associate professor at Harvard Medical School and psychiatric disorders researcher who co-authored the study. Furthermore, “Our gratitude goes to all donors who chose to donate their brain to research to help others suffering from brain disorders, to whom we’d like to dedicate this work.”

Contributions from Key Researchers

In addition, McCarroll teaches at Harvard Medical School and serves as director of genetic neurobiology at the Broad’s Stanley Center for Psychiatric Research. Berretta is the director of the Harvard Brain Tissue Resource Center (HBTRC), which supplied the study’s tissue. The initial author of the study was Emi Ling, a postdoctoral researcher working in McCarroll’s group.

The Role of Synapses in Brain Function

The synapses that connect neurons allow them to exchange impulses with one another, which is primarily how the brain functions. The brain continuously prunes existing synapses and generates new ones. Researchers believe that new synapses maintain our brains’ flexibility. Numerous genetic factors associated with schizophrenia involve genes that support synaptic function, as demonstrated by earlier research conducted by members of McCarroll’s group and worldwide consortia.

Methodology: Single-Nucleus RNA Sequencing and Brain Changes

McCarroll and colleagues used single-nucleus RNA sequencing to analyze gene expression and understand brain variations among individuals. They examined 1.2 million cells from 94 patients with schizophrenia and 97 individuals without the illness.

Astrocytes upregulated specific genes related to synaptic function when neurons increased expression of genes encoding synaptic components. These genes include numerous previously identified risk factors for schizophrenia, which together form the SNAP program. According to the team’s analysis, astrocytes and neurons work together to influence the condition’s hereditary susceptibility.

Surprising Findings in Healthy Individuals

“Astrocytes likely play a role in schizophrenia, as researchers examined gene regulation in different cell types,” Ling said.

Researchers found that SNAP varied significantly in individuals without schizophrenia, suggesting it may influence cognitive variations in healthy individuals. Age significantly influenced this variance, with SNAP decreasing in many older adults, regardless of schizophrenia diagnosis.

Implications for Future Treatments

Understanding SNAP and associated Brain Changes may identify factors that enhance it, aiding schizophrenia treatment and cognitive flexibility in aging.

Exploring Other Disorders

Meanwhile, McCarroll, Berretta, and others are investigating if similar alterations occur in other disorders like depression and bipolar disorder. They seek to determine SNAP’s presence in other brain regions and its effects on cognitive flexibility and learning.

Acknowledgments and Funding

This research received funding from the National Institute of Mental Health, the Stanley Family Foundation, and other organizations.