Strong connections of locally clustered neurons in the upper-layer cortex underlie schizophrenia-related auditory deviance detection.

Overview

1. Department of Cellular Neurobiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
2. Graduate School of Information Science, University of Hyogo, Kobe 650-0047, Japan
3. National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki 444-8585, Japan
4. Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki 444-8585, Japan
5. Laboratory of Animal Resources, Center for Disease Biology and Integrated Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
6. Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
7. The International Research Center for Neurointelligence (IRCN), Institutes for Advanced Study (UTIAS), The University of Tokyo, Tokyo 113-0033, Japan
8. Laboratory for Imaging Neural Dynamics, RIKEN Center for Brain Science, Saitama 351-0198, Japan

Abstract

The detection of unexpected sounds, or auditory deviance detection, is thought to be achieved by comparing prediction signals and sensory inputs in the auditory cortex. This process is markedly impaired in patients with schizophrenia. However, the local circuit properties underlying deviance detection, together with their dysfunction in schizophrenia-related conditions, remain poorly understood. We used two-photon calcium imaging to monitor the population activity of cortical neurons during auditory deviance detection. The deviance-detecting component was predominant in layer 2/3 neurons of the higher-order auditory cortex. The deviance-detecting cells were spatially clustered, exhibited robust synchronization, and constitutively expressed immediate-early genes. In the Del(1.5 megabase)/+ mouse model of 22q11.2 deletion syndrome, a model of schizophrenia, deviance-detecting activity in the upper-layer network was disrupted, accompanied by dysregulated gene expression and selective loss of dendritic spines in immediate-early gene–positive neurons. Our findings support the hypothesis that ensemble activation of this neuronal subpopulation amplifies unexpected inputs, driving error signals that propagate to higher-order cortical areas.

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Data, code, and materials availability

All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials. Original data and software code are available at Zenodo: https://doi.org/10.5281/zenodo.19639395. The Del(1.5 Mb)/+ mice can be provided by A.A. pending scientific review and a completed material transfer agreement with the University of Tokyo. Requests for the Del(1.5 Mb)/+ mice should be submitted to: A.A. at .

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 9 MeSH terms, 4 funders, 65 references.

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This paper

Mizutani, S., Go, Y., Aiba, A., Kasai, K., & Okabe, S. (2026). Strong connections of locally clustered neurons in the upper-layer cortex underlie schizophrenia-related auditory deviance detection. Science advances, 12(33), eaeb4666. https://doi.org/10.1126/sciadv.aeb4666

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