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Excitatory and inhibitory imbalances in the trisynaptic pathway in the hippocampus in schizophrenia: a postmortem ultrastructural study

  • Psychiatry and Preclinical Psychiatric Studies - Original Article
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Abstract

Background

A preponderance of evidence suggests that the hippocampus is a key region of dysfunction in schizophrenia. Neuroimaging and other studies indicate a relationship between hippocampal dysfunction and the degree of psychosis. Clinical data indicate hyperactivity in the hippocampus that precedes the onset of psychosis, and is correlated with symptom severity. In this study, we sought to identify circuitry at the electron microscopic level that could contribute to region-specific imbalances in excitation and inhibition in the hippocampus in schizophrenia. We used postmortem tissue from the anterior hippocampus from patients with schizophrenia and matched controls. Using stereological techniques, we counted and measured synapses, postsynaptic densities (PSDs), and evaluated size, number and optical density of mitochondria and parvalbumin-containing interneurons in key nodes of the trisynaptic pathway. Compared to controls, the schizophrenia group had decreased numbers of inhibitory synapses in CA3 and increased numbers of excitatory synapses in CA1; together, this indicates deficits in inhibition and an increase in excitation. The thickness of the PSD was larger in excitatory synapses in CA1, suggesting greater synaptic strength. In the schizophrenia group, there were fewer mitochondria in the dentate gyrus and a decrease in the optical density, a measure of functional integrity, in CA1. The number and optical density of parvalbumin interneurons were lower in CA3. The results suggest region-specific increases in excitatory circuitry, decreases in inhibitory neurotransmission and fewer or damaged mitochondria. These results are consistent with the hyperactivity observed in the hippocampus in schizophrenia in previous studies.

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Acknowledgements

We would like to thank the Maryland and Alabama Brain Collections and the brain donors and their families.

Funding

Dr. Roberts is a member of the Scientific Advisory Board of the Tourette’s Association of America, and serves as their Brain Tissue Coordinator. The work was partially funded by NIMH MH R21MH127513 (to RCR) and the SPIN program at UAB (KGM).

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Authors and Affiliations

  1. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Sparks Center 835C, 1720 7th Avenue South, Birmingham, AL, 35294, USA

    Charlene B. Farmer, Erica L. Roach, Lily R. Bice, Madeleine E. Falgout, Kattia G. Mata, Joy K. Roche & Rosalinda C. Roberts

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  1. Charlene B. Farmer
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  2. Erica L. Roach
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  3. Lily R. Bice
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  4. Madeleine E. Falgout
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  5. Kattia G. Mata
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  6. Joy K. Roche
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  7. Rosalinda C. Roberts
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Contributions

Author RCR was responsible for experimental design, worked with and mentored authors ELR, LRB, MEF and KGM, identified all synapses and edited the manuscript. Author CBF wrote the first draft of the manuscript, ensured that the appropriate locations were photographed, performed the electron microscopic photography, collected data, organized and supervised the students. Author ELR performed the measurements of postsynaptic density. Authors LRB and MEF performed all of the mitochondrial measurements. Author KGM performed all of the immunohistochemical experiments and analysis. Author JKR cut the tissue for electron microscopy and verified proper location. Manuscript section input was also performed by authors ELR, LRB and MEF.

Corresponding author

Correspondence to Rosalinda C. Roberts.

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Farmer, C.B., Roach, E.L., Bice, L.R. et al. Excitatory and inhibitory imbalances in the trisynaptic pathway in the hippocampus in schizophrenia: a postmortem ultrastructural study. J Neural Transm 130, 949–965 (2023). https://doi.org/10.1007/s00702-023-02650-5

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