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Impaired hippocampal circuitry and memory dysfunction in schizophrenia

Nature Mental Health volume 3, pages 332–345 (2025)Cite this article

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Abstract

Pattern separation and pattern completion are opposing yet complementary components of mnemonic processing that rely heavily on the hippocampus. It has been shown that processing within the dentate gyrus (DG) subfield promotes pattern separation while operations within the CA3 subfield are important for pattern completion. Schizophrenia has been associated with anatomical and functional hippocampal abnormalities, including within the DG and CA3. We hypothesized that an impairment in hippocampal circuitry in individuals with first-episode schizophrenia leads to deficits in pattern separation (mnemonic discrimination) and pattern completion (recognition memory), that these deficits contribute to delusions and that antipsychotic treatment improves circuit functioning. We measured behavioral and neural responses during the identification of new, repeated and similar stimuli using high-resolution fMRI in 45 medication-free or minimally treated individuals with first-episode schizophrenia (FES) and 49 matched healthy controls (HC). We found recognition memory and pattern separation deficits in FES and a negative association between memory performance and the severity of delusions. Neural analyses revealed deficits in BOLD responses in the hippocampus during mnemonic discrimination in FES compared with HC. Importantly, by investigating the association between trial-level neural activity and behavior before and after treatment, we found that antipsychotics normalized DG activity during pattern separation. Last, trial-level cortical responses during mnemonic discrimination predicted performance in FES at baseline, suggesting a compensatory role. This case-control study provides important insight into the impact of schizophrenia and antipsychotic treatment on memory systems and uncovers systems-level contributions to pattern separation and pattern completion.

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Fig. 1: Hypotheses and task design.
Fig. 2: Behavioral performance in Session 1.
Fig. 3: Percent signal change during NN, OO and SS.
Fig. 4: Results of trial-level mixed-effects linear models in Session 1.
Fig. 5: Normalization of DG and CA3 functions after antipsychotic treatment.
Fig. 6: Results of trial-level mixed-effects linear models predicting the success in response to similar items in cortical ROIs in Session 1.

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Data availability

The dataset collected for this work includes self-reported demographic information, clinical evaluations and neurocognitive and functional neuroimaging data from individuals with first-episode psychosis. The original dataset contained identifying information (required for the process of clinical care), and even after de-identifying the data, there might be a possibility of revelation of the identity of individuals with uncommon characteristics. Thus, the data will be available on request to users who provide a data-sharing agreement that ensures protecting the anonymity of participants through safe handling and storing of data according to our protocol. Data access shall be requested by contacting the corresponding author (ld24@columbia.edu) and will be responded to promptly.

Code availability

Codes to perform the main analyses of the paper are available in the following GitHub repository: https://github.com/azadbood/schizo_hipp_circuit_ps.

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Acknowledgments

We thank C. Cather for training of raters, W. Yu for her comments on the analyses and T. Hainmueller for his comments on the manuscript. This work was supported by NIH grant R01MH112733 awarded to D.C.G. and L.D.

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Author notes

  1. These authors contributed equally: Jijun Wang, Donald C. Goff, Lila Davachi.

Authors and Affiliations

  1. Department of Psychology, Columbia University, Columbia, NY, USA

    Asieh Zadbood, Camille Gasser & Lila Davachi

  2. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yingying Tang, Hao Hu, Tianhong Zhang, Yawen Hong & Jijun Wang

  3. Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA

    Wenjun Su, Gillian Capichioni & Donald C. Goff

  4. Department of Developmental and Behavioural Pediatric and Child Primary Care, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Shuwen Yang

  5. Suzhou Guangji Hospital, The Affiliated Guangji Hospital of Soochow University, Suzhou, China

    Junjie Wang, Li Hui & Qiufang Jia

  6. Department of Psychology and Neuroscience, Temple University, Philadelphia, PA, USA

    Vishnu P. Murty

  7. Weill Cornell Institute of Geriatric Psychiatry, Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA

    Oded Bein

  8. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA

    Michael F. Green

  9. VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    Michael F. Green

  10. Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    Donald C. Goff & Lila Davachi

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Contributions

L.D. and D.C.G. and A.Z. conceptualized the study and analyses. A.Z., Y.T., W.S. curated the data. A.Z. performed the formal analyses. Y.T., W.S., H.H., S.Y., J.W., V.P.M., C.G., O.B., L.H., Q.J., T.Z., Y.H. performed the investigation (including task administration and clinical and neuroimaging data collection). G.C. was the project administrator. M.F.G. provided the cognitive battery. L.D. and D.C.G. aquired the funding. J.W., D.C.G., and L.D. supervised the study. A.Z, L.D. and D.C,G. conducted the visualization. A.Z., L.D., and D.C.G. wrote the original manuscript draft. All authors reviewed and edited the manuscript.

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Correspondence to Asieh Zadbood or Lila Davachi.

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Zadbood, A., Tang, Y., Su, W. et al. Impaired hippocampal circuitry and memory dysfunction in schizophrenia. Nat. Mental Health 3, 332–345 (2025). https://doi.org/10.1038/s44220-024-00376-1

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