What Secrets Do Synaptic Changes Reveal About the Brain?

Researchers at the Broad Institute of MIT and Harvard, Harvard Medical School, and McLean Hospital have uncovered a striking similarity in gene activity related to synaptic changes in the brain tissue of schizophrenia patients and elderly individuals. This discovery suggests a shared biological foundation for cognitive impairment in both groups.

The Study Overview

In a report published in Nature, the researchers detailed their examination of gene expression in over one million individual cells from the postmortem brain tissues of 191 individuals. They found that both persons with schizophrenia and older adults—without schizophrenia—exhibit lower expression of genes that support synapses, the junctions between neurons. In contrast, healthy younger individuals showed higher expression levels of these genes.

Additionally, the researchers identified tightly synchronized variations in gene expression across the two cell types. When neurons decreased the expression of synaptic-related genes, astrocytes—supportive glial cells—also lowered the expression of a separate set of synaptic-supporting genes.

The team named this coordinated alteration the Synaptic Neuron and Astrocyte Program (SNAP). In healthy young individuals, SNAP gene expression in neurons and astrocytes increased or decreased in a coordinated manner.

Insights from the Research Team

“Science often focuses on the specific genes expressed by each cell type independently,” said Steve McCarroll, a co-senior author of the paper and a member of the Broad Institute. “However, our analysis of brain tissue from numerous individuals, combined with machine-learning studies, revealed a more extensive system. These cell types do not operate in isolation but rather work together in close collaboration. The strength of these relationships was astonishing.”

The Implications of Cognitive Impairment

Schizophrenia is well-known for inducing hallucinations and delusions, which can be somewhat managed with medication. However, it also leads to significant cognitive decline, for which effective treatments are lacking—a condition that often accompanies aging. The new findings indicate that cognitive changes in schizophrenia and aging may arise from similar cellular and molecular brain alterations.

“Our ability to detect coordination between astrocytes and neurons in both schizophrenia and aging required studying tissue samples from a large number of individuals,” stated Sabina Berretta, a co-senior author of the study, associate professor at Harvard Medical School, and a researcher specializing in psychiatric disorders. “We extend our gratitude to all the donors who chose to contribute their brain tissue to research, helping others suffering from brain disorders. We dedicate this work to them.”

Understanding Synaptic Neuronal Communication

The brain primarily functions through the communication between neurons via synapses. It continuously creates new synapses while pruning existing ones. Scientists believe that the formation of new synapses contributes to brain flexibility. Previous research suggests that many genetic factors linked to schizophrenia affect genes involved in synaptic function, including McCarroll’s group findings.

In their study, McCarroll, Berretta, and colleagues used single-nucleus RNA sequencing to analyze gene expression variations among individuals. They examined 1.2 million cells from 94 individuals with schizophrenia and 97 without.

Key Findings on SNAP

The research revealed that when neurons increased the expression of genes encoding synaptic components, astrocytes simultaneously heightened their expression of a specific set of genes involved in synaptic activity. The genes constituting the SNAP program included numerous established risk factors for schizophrenia. The investigations confirmed that both neurons and astrocytes play a role in the genetic predisposition to the illness.

“While science has long recognized the importance of neurons and synapses in schizophrenia risk, we found that framing the question differently—focusing on the genes regulated dynamically by each cell type—revealed astrocytes’ likely involvement,” noted Emi Ling, the study’s first author.

Variability in Synaptic Changes Among Healthy Individuals

Unexpectedly, the researchers discovered significant differences in SNAP even among individuals without schizophrenia. This variation was largely attributed to age, as SNAP expression decreased in many older individuals, both with and without schizophrenia.

Future Directions for Synaptic Research

With a deeper understanding of SNAP, McCarroll believes it will be possible to identify lifestyle factors that positively influence SNAP and develop medications aimed at stimulating SNAP to treat cognitive impairments associated with schizophrenia or enhance cognitive flexibility in aging individuals.

McCarroll, Berretta, and their team are investigating if similar changes occur in bipolar disorder and depression. They also aim to understand how SNAP manifests in different brain regions and its influence on learning and cognitive flexibility.