Synaptic Pathology in Schizophrenia and Mood Disorders

Synaptic pathology is increasingly recognised as central to the development and symptomatology of schizophrenia and mood disorders. In schizophrenia, a convergence of genetic risk variants and environmental insults appears to render synaptic connections vulnerable to excessive elimination, leading to reduced synaptic density in key cortical and limbic regions. This loss is thought to underlie cognitive deficits, negative symptoms and dysregulated dopaminergic signalling. Mood disorders, including bipolar disorder and major depression, show more subtle or regionally specific synaptic alterations, such as reduced dendritic spine density and changes in postsynaptic scaffolding proteins within prefrontal and limbic circuits. Evidence derives from post-mortem quantification of synaptic proteins, in vivo neuroimaging of grey matter and molecular markers of synapse number, and cellular models that reproduce patient-specific synaptic deficits. Together, these lines of research highlight both common pathways—such as dysregulated synaptic plasticity and immune-mediated pruning—and disorder-specific patterns of synaptic dysfunction, opening avenues for targeted therapeutic intervention.

Research from Nature Portfolio

Recent studies employing synaptic density imaging and circuit-level analysis have provided direct in vivo evidence for synaptic alterations in schizophrenia. Using positron emission tomography of the vesicle protein SV2A, investigators have demonstrated significantly lower synaptic terminal density in frontal and anterior cingulate cortices of patients, an effect that appears independent of antipsychotic exposure. Complementary rodent work has shown that dopamine D2 receptor activity in the adolescent anterior cingulate cortex regulates synaptic pruning via mTOR signalling; disrupted pruning in this model leads to hyper-glutamatergic function and anxiety-like behaviours in adulthood. These findings together reinforce a model in which neuromodulator-driven synaptic refinement during adolescence plays a pivotal role in shaping circuits that, when perturbed, contribute to the onset of psychotic and affective symptoms.

Synaptic Pathology in Schizophrenia and Mood Disorders publication trend

The graph below shows the total number of articles in synaptic pathology in schizophrenia and mood disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Synaptic pruning: The developmental process of removing surplus synaptic connections to refine neural circuits.

Synaptic vesicle glycoprotein 2A (SV2A): A presynaptic membrane protein used as an in vivo marker of synaptic density in PET imaging.

Postsynaptic density (PSD): A specialised protein assembly beneath the postsynaptic membrane that organises neurotransmitter receptors and signalling molecules.

Microglia: Central nervous system immune cells that mediate synaptic elimination through phagocytosis and complement recognition.

Induced pluripotent stem cells (iPSC): Adult cells reprogrammed to a pluripotent state and differentiated into neurons to model patient-specific synaptic pathology.

References

1. Synaptic Terminal Density Early in the Course of Schizophrenia: An In Vivo UCB-J Positron Emission Tomographic Imaging Study of SV2A. Biological Psychiatry (2023).
2. Dopamine D2 receptor regulates cortical synaptic pruning in rodents. Nature Communications (2021).
3. The synaptic hypothesis of schizophrenia version III: a master mechanism. Molecular Psychiatry (2023).
4. Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures. Molecular Psychiatry (2018).
5. The neuropathology of bipolar disorder: systematic review and meta-analysis. Molecular Psychiatry (2018).