Researchers, including a Rutgers professor, have gained clearer insight into the biological changes associated with schizophrenia by directly measuring synaptic connections in the living human brain. The team used specialized positron emission tomography (PET) imaging to examine these crucial points of communication between brain cells.
The study, published in molecular psychiatry, was led by senior authors Avram Holmes, associate professor of psychiatry at the Robert Wood Johnson Medical School and senior faculty member of the Center for Advanced Research in Human Brain Imaging within the Rutgers Brain Health Institute, and Rajiv Radhakrishnan, associate professor of psychiatry and radiology and biomedical imaging at Yale University. The first author, Sidhant Chopra, a former postdoctoral fellow at the Holmes Laboratory, is a McKenzie researcher at Orygen, Australian Center of Excellence in Youth Mental Healthand the University of Melbourne in Australia.
Measure synaptic connections in the brain
Synapses are small junctions that allow brain cells to communicate with each other through neural circuits. Problems related to these connections are thought to play a role in the cognitive and emotional symptoms of schizophrenia. Until now, however, scientists have had a limited understanding of exactly where synaptic loss occurs in the brains of living people because conventional imaging methods, such as MRI, cannot specifically measure synapses.
The research involved 122 people, including 29 diagnosed with schizophrenia, making it one of the largest synaptic density PET imaging studies conducted to date. Compared to healthy participants, people with schizophrenia showed a pronounced and widespread reduction in synaptic connections in various parts of the brain. These included frontal and temporal regions, as well as areas involved in memory and emotions. The loss was also considerably greater on the left side of the brain than on the right.
The researchers found that this synaptic pattern did not match the changes in brain volume typically seen on standard MRI scans. That distinction suggests that synaptic loss and changes in brain volume may reflect separate biological processes rather than two imaging methods that capture the same underlying change.
A molecular pattern behind synaptic loss
The team also found that brain regions showing the greatest synaptic losses tended to contain high concentrations of receptors for important neurotransmitters, such as serotonin, gamma-aminobutyric acid and glutamate. The finding suggests that molecular characteristics of individual brain regions may influence their vulnerability to changes associated with schizophrenia.
To explore how synaptic loss might move through the brain, the researchers used computer simulations based on the brain’s structural connections. Their modeling identified an area in the left frontal lobe as a likely starting point from which synaptic loss could spread to connected regions.
“These findings suggest that in schizophrenia, synaptic loss is not random,” Chopra said. “Rather, it follows the molecular and connectivity architecture of the brain, 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 regenerate synapses,” Holmes added.
Towards more precise treatments for schizophrenia
The researchers said future work will build on these results by investigating how synaptic loss changes over time and how it responds to clinical treatments. A better understanding of that progression could ultimately help researchers develop more precise and personalized approaches to schizophrenia care.