Schizophrenia's synaptic loss follows the brain's molecular and connectivity architecture, PET study finds
核心洞察
A PET imaging study of 122 participants, including 29 people with schizophrenia (搜索), found widespread and pronounced reductions in synaptic density across frontal and temporal regions and areas involved in memory and emotion.
Synaptic loss was substantially greater in the left hemisphere than the right, and this pattern did not match the brain-volume changes typically seen on standard MRI scans.
Brain regions with the greatest synaptic loss tended to be rich in receptors for serotonin, GABA, and glutamate (搜索), suggesting a region's molecular makeup influences its vulnerability.
A specialized positron emission tomography (PET) imaging study has mapped where synaptic connections are most reduced in people with schizophrenia (搜索) and identified a possible region from which the damage begins to spread. The findings, published in Molecular Psychiatry, suggest that synaptic loss in schizophrenia is not random but instead follows the brain's molecular and connectivity architecture.
The study was led by senior authors Avram Holmes, associate professor of psychiatry at Robert Wood Johnson Medical School and core faculty member of the Center for Advanced Human Brain Imaging Research within the Rutgers Brain Health Institute (搜索), and Rajiv Radhakrishnan, associate professor of psychiatry and radiology and biomedical imaging at Yale University (搜索). First author Sidhant Chopra, formerly a postdoctoral fellow in the Holmes Lab, is a McKenzie Research Fellow at Orygen, Australia's Centre of Excellence in Youth Mental Health, and the University of Melbourne.
Measuring synaptic connections in the living brain
Synapses are tiny junctions that allow brain cells to communicate with one another across neural circuits. Problems involving these connections are believed to play a role in the cognitive and emotional symptoms of schizophrenia (搜索). 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 magnetic resonance imaging cannot specifically measure synapses.
The research involved 122 people, including 29 diagnosed with schizophrenia (搜索), making it one of the largest synaptic density PET imaging studies conducted so far. Compared with healthy participants, people with schizophrenia showed a pronounced and widespread reduction in synaptic connections across several parts of the brain, including frontal and temporal regions as well as areas involved in memory and emotion.
A striking left-brain imbalance
The loss was considerably greater on the left side of the brain than on 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 (搜索). 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.
Researchers also found that this synaptic pattern did not match the changes in brain volume typically seen with standard MRI scans. That distinction suggests synaptic loss and changes in brain volume may reflect separate biological processes rather than two imaging methods capturing the same underlying change.
Why certain brain regions are vulnerable
The team discovered that the brain regions showing the greatest synaptic losses tended to contain high concentrations of receptors for important neurotransmitters, including serotonin, gamma-aminobutyric acid (GABA), and glutamate (搜索). These three neurotransmitter systems help regulate mood, perception, learning, and the balance between neural excitation and inhibition. The finding suggests that the molecular characteristics of individual brain regions may influence how vulnerable they are to changes associated with schizophrenia (搜索), and could help explain why the disorder affects some neural circuits more strongly than others.
Tracing where the damage may begin
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 into connected regions.
"These findings suggest that in schizophrenia (搜索), 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.
Toward more precise schizophrenia treatments
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. 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 (搜索) progresses. Longer studies that follow patients over time will be needed to determine how illness duration, treatment, and other factors influence the process. A better understanding of that progression could ultimately help researchers develop more precise and personalized approaches to schizophrenia care.