Restoring synaptic balance in schizophrenia: Insights from a thalamo-cortical conductance-based model
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Abstract
BACKGROUND AND HYPOTHESIS: The dysconnectivity hypothesis of schizophrenia suggests that atypical neural communication underlies the disorder's diverse symptoms. Building on this framework, we propose that specific synaptic disturbances within thalamo-cortical circuits contribute to an imbalance in excitation and inhibition, leading to alteration in oscillations. Our study investigates these alterations and explores whether synaptic restoration can remediate neural activity of schizophrenia and align it with healthy patterns. STUDY DESIGN: We analyzed magnetoencephalography data from schizophrenia patients and healthy controls using dynamic causal modeling to identify synaptic differences in thalamo-cortical circuits. The analysis focused on N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), gamma-aminobutyric acid type A (GABA-A), and gamma-aminobutyric acid type B (GABA-B) receptor-mediated connections. In silico synaptic restoration analysis simulated the effects of targeted adjustments to these receptor-mediated connections to assess whether altered neural activity in schizophrenia could be restored to match control patterns. STUDY RESULTS: Schizophrenia patients showed statistically significant differences in increased NMDA receptor excitation in superficial pyramidal neurons and reduced GABA-B receptor inhibition between interneurons and pyramidal cells. Parameter recovery analysis revealed limitations for these specific parameters, suggesting that receptor-level interpretations should be made with caution. The in silico synaptic restoration analysis indicated that coordinated modifications across multiple synaptic pathways could potentially remediate neural activity to resemble healthy controls. CONCLUSIONS: This restoration approach suggests the complex nature of synaptic dysfunction in schizophrenia may involve coordinated changes across multiple synaptic parameters rather than isolated alterations. While our findings provide preliminary evidence extending the dysconnectivity theory of schizophrenia, the parameter recovery limitations suggest that specific receptor claims should be interpreted with caution.
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NMDA receptor dysfunction, which is implicated in schizophrenia, affects synaptic gain and thus the encoding of prediction error signals.
“NMDA receptor dysfunction, which is implicated in schizophrenia, affects synaptic gain and thus the encoding of prediction error signals (26).”
From Predictive coding and neurocomputational psychiatry: a mechanistic framework for understanding mental disorders (2026) · cites this paper as [26]
The Introduction (page not provided) implicates NMDA receptor dysfunction in schizophrenia, and Discussion §4.2 reports altered NMDA-mediated excitation in superficial pyramidal cells. The paper does not connect that alteration to the encoding of prediction error signals, so the claimed consequence is unsupported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredComputational psychiatry studies have used conductance-based neural mass models to infer synaptic changes in disorders like schizophrenia from M/EEG recordings.
“Computational psychiatry studies have done exactly this – for instance, using conductance-based neural mass models to infer synaptic changes in disorders like schizophrenia from M/EEG recordings (25, 26).”
From Predictive coding and neurocomputational psychiatry: a mechanistic framework for understanding mental disorders (2026) · cites this paper as [26]
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Bianciardi, B., Mastek, H., Franka, M., & Uhlhaas, P. J. (2024) · Schizophrenia Bulletin · doi:10.1093/schbul/sbae090 · Cited by 5 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [30]Robinson S, Vrba J, Yoshimoto T, et al. Recent Advances in Biomagnetism. Sendai: Tohoku University Press; 1999.
Cited by
Sorted by citations
Shaw, A. D., Sumner, R. L., & Berndt, L. C. S. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1713833 · Cited by 9 · see citing works
Self-citation
- Authors
- Berndt, L. C. S., Singh, K. D., & Shaw, A. D.
- Affiliations
- University of Exeter (GB)
- Cardiff University (GB)
- Corresponding author
- Berndt, Lioba C S
- Venue
- Schizophrenia Bulletin
- Publisher
- Oxford University Press (OUP)
- Published
- 2025-09-11
- Volume
- 52
- Issue
- 4
- ISSN
- 0586-7614 (ISSN-L)
- 1745-1701
- PMC
- PMC13391648
- OpenAlex
- W4414152921
- Cited by
- 3
- References
- 97
- Citations by year
- 2026: 2 · 2025: 1
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Schizophrenia Bulletin (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Funders
- Schools of Psychology and Medicine at Cardiff University and the School of Psychology at University of Exeter (MRC/EPSRC, MR/K005464/1, 226709/Z/22/Z)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- schizophrenia, thalamocortical circuits
- MeSH terms
- Adult, Cerebral Cortex, Female, Humans, Male, Middle Aged, Models, Neurological, Nerve Net, Neural Pathways, Schizophrenia, Synapses, Thalamus, Magnetoencephalography, Receptors, N-Methyl-D-Aspartate, Receptors, GABA-B
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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