Summary: A new study revealed shared cellular and molecular changes in the brains of people with schizophrenia and older adults, pointing to a common biological basis for cognitive impairments in these groups.

The study analyzed gene expression in over a million cells from 191 individuals, uncovering a coordinated reduction in genes supporting synaptic connections by neurons and astrocytes, dubbed the Synaptic Neuron and Astrocyte Program (SNAP). This synchronization indicates a closely coordinated system affecting brain function, with potential implications for understanding and treating cognitive decline in schizophrenia and aging.

The discovery of SNAP offers insights into the brains synaptic dynamics and raises hope for identifying interventions to preserve cognitive functions.

Key Facts:

Source: Broad Institute

Researchers from the Broad Institute of MIT and Harvard, Harvard Medical School, and McLean Hospital have uncovered a strikingly similar suite of changes in gene activity in brain tissue from people with schizophrenia and from older adults.

These changes suggest a common biological basis for the cognitive impairment often seen in people with schizophrenia and in the elderly.

In a study published inNature, the team describes how they analyzed gene expression in more than a million individual cells from postmortem brain tissue from 191 people.

They found 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.

They also discovered tightly synchronized gene expression changes in the two cell types: when neurons decreased the expression of certain genes related to synapses, astrocytes similarly changed 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, saidSteve 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.

Schizophrenia is well-known for causing hallucinations and delusion, which can be at least partly treated with medications. But it also causes debilitating cognitive decline, which has no effective treatments and is common in aging as well.

The new findings suggest that the cognitive changes in both conditions might involve similar cellular and molecular alterations in the brain.

To detect coordination between astrocytes and neurons in schizophrenia and aging, we needed to study tissue samples from a very large number of individuals, said Sabina Berretta, a co-senior author of the study, an associate professor at Harvard Medical School, and a researcher in the field of psychiatric disorders.

Our gratitude goes to all donors who chose to donate their brain to research to help others suffering from brain disorders and to whom wed like to dedicate this work.

McCarroll is also director of genomic neurobiology for the BroadsStanley Center for Psychiatric Researchand a professor at Harvard Medical School. Berretta also directs theHarvard Brain Tissue Resource Center(HBTRC), which provided tissue for the study. Emi Ling, a postdoctoral researcher in McCarrolls lab, was the studys first author.

SNAP insights

The brain works in large part because neurons connect with other neurons at synapses, where they pass signals to one another. The brain constantly forms new synapses and prunes old ones.

Scientists think new synapses help our brains stay flexible, and studies including previous efforts by scientists inMcCarrolls labandinternational consortia have shown that many genetic factors linked to schizophrenia involve genes that contribute to the function of synapses.

In the new study, McCarroll, Berretta, and colleagues used single-nucleus RNA sequencing, which measures gene expression in individual cells, to better understand how the brain naturally varies across individuals. They analyzed 1.2 million cells from94 people with schizophrenia and 97 without.

They found that when neurons boosted expression of genes that encode parts of synapses, astrocytes increased the expression of a distinct set of genes involved in synaptic function.

These genes, which make up the SNAP program, included many previously identified risk factors for schizophrenia. The teams analyses indicated that both neurons and astrocytes shape genetic vulnerability for the condition.

Science has long known that neurons and synapses are important in risk for schizophrenia, but by framing the question a different way asking what genes each cell type regulates dynamically we found that astrocytes too are likely involved, said Ling.

To their surprise, the researchers also found 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, McCarroll says he hopes 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.

In the meantime, McCarroll, Berretta, and their team are working to understand if these changes are present in other conditions such as bipolar disorder and depression. They also aim to uncover the extent to which SNAP appears in other brain areas, and how SNAP affects learning and cognitive flexibility.

Funding: This work was supported by the Stanley Family Foundation, the Simons Collaboration on Plasticity and the Aging Brain, and the National Institute of Mental Health and the National Human Genome Research Institute at the National Institutes of Health.

Author: Allessandra DiCorato Source: Broad Institute Contact: Allessandra DiCorato Broad Institute Image: The image is credited to Neuroscience News

Original Research: Open access. Concerted neuron-astrocyte program declines in ageing and schizophrenia by Steve McCarroll et al. Nature

Abstract

Concerted neuron-astrocyte program declines in ageing and schizophrenia

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between peoples cortical neurons and cortical astrocytes.

We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 2297years, including healthy individuals and people with schizophrenia.

Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP).

In schizophrenia and ageingtwo conditions that involve declines in cognitive flexibility and plasticitycells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees.

The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology.

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Schizophrenia and Aging Share Brain Changes - Neuroscience News