ReviewMolecular psychiatry2023
The synaptic hypothesis of schizophrenia version III: a master mechanism.
Review in Molecular psychiatry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 128 papers, 5 of them syntheses that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
128 citing papers in PubMed, 5 syntheses or guidelines pooled it, 176 citations in OpenAlex.
- Multimodal microglial and kynurenine pathway alterations across the affective-psychosis spectrum: a systematic review of patterns, heterogeneity, and dimensional implications.Molecular psychiatry · 2026Pooled it
- Inflammatory cytokine alterations in genetic and clinical high risk groups of psychosis: a systematic review and network meta-analysis.Psychological medicine · 2026Pooled it
- Molecular and topographic mapping of antipsychotic effects: a meta-analysis of postsynaptic density proteins in animal models with translational implications.Molecular psychiatry · 2026Pooled it
- Uncovering convergence and divergence between autism and schizophrenia using genomic tools and patients' neurons.Molecular psychiatry · 2025Pooled it
- EANM perspective on clinical PET and SPECT imaging in schizophrenia-spectrum disorders: a systematic review of longitudinal studies.European journal of nuclear medicine and molecular imaging · 2025Pooled it
- A study on Mahjong intervention to improve cognitive impairment in patients with schizophrenia: a pilot, single-blind, randomized, controlled trial.BMC psychiatry · 2025Trial
- Antipsychotics cause reversible structural brain changes within one week.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Trial
- Mapping topological abnormalities in cortical similarity networks to schizophrenia-associated gene expression.Dialogues in clinical neuroscience · 2026Article
- An etiological approach to psychosis: potential benefits for treatment, research and prevention.World psychiatry : official journal of the World Psychiatric Association (WPA) · 2026Article
- Rethinking schizophrenia: insights from genomics and implications for research.Molecular psychiatry · 2026Review
- Estimating protein isoform abundances with [Formula: see text].Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Mismatch negativity matures in adolescence and without sensitivity to microglial depletion.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Polygenic risk score for neurodevelopmental disorders and cognitive impairment at long-term follow-up of first-episode psychosis.European archives of psychiatry and clinical neuroscience · 2026Article
- Schizophrenia: Converging Neurobiological Mechanisms and Emerging Therapeutic Strategies.Biomolecules · 2026Review
- Loss of schizophrenia risk gene XPO7 disrupts neuronal excitability and network regularity via altered NaMolecular psychiatry · 2026Article
- Toward a Pluralistic Model for the Schizophrenia Spectrum-Dopamine and Beyond.JAMA psychiatry · 2026Review
- Childhood adversity and psychotic-like experiences in adolescence: Investigating a pathway via disrupted pubertal and grey matter development.JCPP advances · 2026Article
- The NLRP3 inflammasome: pathophysiology and therapeutic implications for schizophrenia and neuropsychiatric disorders.Molecular psychiatry · 2026Review
- Increased RHOA expression in peripheral blood mononuclear cells of patients with acute schizophrenia.Molecular biology reports · 2026Article
- The microglial TREM2 receptor programs hippocampal development in a mouse model of childhood deprivation.Brain, behavior, and immunity · 2026Article
68 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
The synaptic hypothesis of schizophrenia has been highly influential. However, new approaches mean there has been a step-change in the evidence available, and some tenets of earlier versions are not supported by recent findings. Here, we review normal synaptic development and evidence from structural and functional imaging and post-mortem studies that this is abnormal in people at risk and with schizophrenia. We then consider the mechanism that could underlie synaptic changes and update the hypothesis. Genome-wide association studies have identified a number of schizophrenia risk variants converging on pathways regulating synaptic elimination, formation and plasticity, including complement factors and microglial-mediated synaptic pruning. Induced pluripotent stem cell studies have demonstrated that patient-derived neurons show pre- and post-synaptic deficits, synaptic signalling alterations, and elevated, complement-dependent elimination of synaptic structures compared to control-derived lines. Preclinical data show that environmental risk factors linked to schizophrenia, such as stress and immune activation, can lead to synapse loss. Longitudinal MRI studies in patients, including in the prodrome, show divergent trajectories in grey matter volume and cortical thickness compared to controls, and PET imaging shows in vivo evidence for lower synaptic density in patients with schizophrenia. Based on this evidence, we propose version III of the synaptic hypothesis. This is a multi-hit model, whereby genetic and/or environmental risk factors render synapses vulnerable to excessive glia-mediated elimination triggered by stress during later neurodevelopment. We propose the loss of synapses disrupts pyramidal neuron function in the cortex to contribute to negative and cognitive symptoms and disinhibits projections to mesostriatal regions to contribute to dopamine overactivity and psychosis. It accounts for the typical onset of schizophrenia in adolescence/early adulthood, its major risk factors, and symptoms, and identifies potential synaptic, microglial and immune targets for treatment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.