Advanced positron emission tomography (PET) imaging has revealed widespread loss of synaptic connections across the brains of people living with schizophrenia, offering new insight into the biological mechanisms underlying the disorder and identifying potential targets for future therapies.

The findings, published in Molecular Psychiatry, come from one of the largest PET imaging studies of synaptic density conducted to date and suggest that the loss of synapses follows distinct patterns linked to the brain’s molecular architecture rather than occurring randomly.

The research was led by investigators from Rutgers University, Yale University and Australia’s Orygen Centre of Excellence in Youth Mental Health.

Synapses are the specialised junctions that allow brain cells to communicate with one another and play a central role in learning, memory and cognition. Although disruption of these connections has long been suspected to contribute to schizophrenia, conventional imaging techniques such as magnetic resonance imaging (MRI) cannot directly measure synaptic density in living patients.

Using specialised PET imaging, the researchers examined 122 participants, including 29 people diagnosed with schizophrenia. Compared with healthy volunteers, individuals with schizophrenia showed widespread reductions in synaptic density across multiple brain regions involved in executive function, memory, emotion and cognition. The left hemisphere was found to be more severely affected than the right.

Importantly, the researchers found that the pattern of synaptic loss differed from the structural brain changes typically detected using MRI, suggesting that the two represent distinct biological processes rather than different ways of measuring the same disease.

The study also found that the areas showing the greatest synaptic loss were rich in receptors involved in key neurotransmitter systems, including serotonin, gamma-aminobutyric acid (GABA) and glutamate. This finding suggests that the brain’s molecular characteristics may influence which regions are most vulnerable during the development of schizophrenia.

Computer modelling of the brain’s structural networks further identified a region within the left frontal lobe as a potential origin from which synaptic loss may spread to connected brain regions.

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

Avram Holmes, associate professor of psychiatry at Rutgers Robert Wood Johnson Medical School and senior author of the study, added: “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.”

The researchers said future work will investigate how synaptic loss progresses over time and whether it can be modified through therapeutic intervention. As interest grows in treatments designed to preserve or restore synaptic function, the ability to directly measure these changes in living patients could help improve both disease monitoring and the development of new therapies for schizophrenia.