Schizophrenia may alter the brain according to a hidden molecular pattern. Regions rich in key neurotransmitter receptors appeared especially vulnerable, offering new clues about why certain neural circuits are affected more than others. Credit: Shutterstock

Schizophrenia may leave a distinctive biological footprint across the brain’s communication network.

Using specialized PET imaging, researchers have mapped where synaptic connections are most reduced in people with schizophrenia and identified a possible region from which the damage begins to spread.

The study, which involved a Rutgers professor, was published in Molecular Psychiatry.

Synapses are microscopic contact points that allow neurons to exchange information. They are essential for memory, attention, emotion, and decision-making, all of which can be disrupted in schizophrenia. Scientists have long suspected that abnormal synapse development or loss contributes to the disorder, but observing these connections in living people has been difficult. Standard MRI scans can measure changes in brain structure, but they cannot directly estimate the number of synapses.

The researchers used a specialized form of positron emission tomography (PET) to examine synaptic density in 122 participants, including 29 people diagnosed with schizophrenia. It was one of the largest studies of its kind conducted to date.

A Striking Left Brain Imbalance

The scans revealed a broad reduction in synaptic connections among participants with schizophrenia. The greatest differences appeared across frontal and temporal regions, as well as areas involved in memory and emotional processing. The effect was also strongly uneven, with the left hemisphere showing substantially greater synaptic loss than the right.

That asymmetry may be especially important because the left side of the brain contains networks involved in language, planning, and other functions that are often affected in schizophrenia. The findings do not show that reduced synaptic density directly causes specific symptoms, but they offer a clearer picture of how widely the disorder may alter communication between brain cells.

The synaptic pattern also differed from the changes in brain volume commonly seen on MRI scans. This indicates that reduced synaptic density and structural tissue loss may represent separate biological processes rather than different measurements of the same underlying damage.

Why Certain Brain Regions Are Vulnerable

Some brain regions appeared particularly vulnerable. Areas with the greatest synaptic reductions were normally rich in receptors for serotonin, gamma-aminobutyric acid, and glutamate, three neurotransmitter systems that help regulate mood, perception, learning, and the balance between neural excitation and inhibition.

This relationship suggests that a region’s molecular makeup may influence how susceptible it is to synaptic disruption. It could also help explain why schizophrenia affects some neural circuits more strongly than others.

To explore how the changes might develop, the researchers used computer models to simulate the spread of synaptic loss through the brain’s structural connections. The models identified a region in the left frontal lobe as a possible starting point, with abnormalities potentially extending into other connected areas over time.

Tracing Where the Damage May Begin

“These findings suggest that in schizophrenia, synaptic loss is not random,” Chopra said. “Rather, it follows the brain’s molecular and connectivity architecture, which could eventually help identify where and how to intervene.”

“This detailed mapping of synaptic vulnerability could eventually help identify where and how to intervene to preserve or restore brain function, such as emerging therapies to prevent and regrow synapses,” Holmes added.

Because the study captured only a single point in time, it cannot yet reveal when synaptic changes begin or whether they become more severe as schizophrenia progresses. Longer studies that follow patients over time will be needed to determine how illness duration, treatment, and other factors influence the process.

Reference: “Widespread synaptic density loss in schizophrenia follows molecular and network architecture” by Sidhant Chopra, Patrick D. Worhunsky, Mika Naganawa, Xi-Han Zhang, Ashlea Segal, Loïc Labache, Edwina Orchard, Vanessa Cropley, Stephen Wood, Gustavo A. Angarita, Kelly Cosgrove, David Matuskey, Nabeel B. Nabulsi, Yiyun Huang, Richard E. Carson, Irina Esterlis, Patrick D. Skosnik, Deepak C. D’Souza, Avram J. Holmes and Rajiv Radhakrishnan, 25 June 2026, Molecular Psychiatry.
DOI: 10.1038/s41380-026-03717-x

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