Restoring synaptic balance in schizophrenia: insights from a thalamo-cortical conductance-based model

Berndt, Lioba C. S., Singh, Krish D. ORCID: https://orcid.org/0000-0002-3094-2475 and Shaw, Alexander D. 2025. Restoring synaptic balance in schizophrenia: insights from a thalamo-cortical conductance-based model. Schizophrenia Bulletin: The Journal of Psychoses and Related Disorders , sbaf149. 10.1093/schbul/sbaf149

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Psychology
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Type: cc-by
Publisher:	Oxford University Press
ISSN:	0586-7614
Date of First Compliant Deposit:	17 September 2025
Date of Acceptance:	30 July 2025
Last Modified:	17 Sep 2025 09:45
URI:	https://orca.cardiff.ac.uk/id/eprint/181143

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