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Inflammation-related pathology in the olfactory epithelium: its impact on the olfactory system in psychotic disorders

Molecular Psychiatry (2024)Cite this article

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Abstract

Smell deficits and neurobiological changes in the olfactory bulb (OB) and olfactory epithelium (OE) have been observed in schizophrenia and related disorders. The OE is the most peripheral olfactory system located outside the cranium, and is connected with the brain via direct neuronal projections to the OB. Nevertheless, it is unknown whether and how a disturbance of the OE affects the OB in schizophrenia and related disorders. Addressing this gap would be the first step in studying the impact of OE pathology in the disease pathophysiology in the brain. In this cross-species study, we observed that chronic, local OE inflammation with a set of upregulated genes in an inducible olfactory inflammation (IOI) mouse model led to a volume reduction, layer structure changes, and alterations of neuron functionality in the OB. Furthermore, IOI model also displayed behavioral deficits relevant to negative symptoms (avolition) in parallel to smell deficits. In first episode psychosis (FEP) patients, we observed a significant alteration in immune/inflammation-related molecular signatures in olfactory neuronal cells (ONCs) enriched from biopsied OE and a significant reduction in the OB volume, compared with those of healthy controls (HC). The increased expression of immune/inflammation-related molecules in ONCs was significantly correlated to the OB volume reduction in FEP patients, but no correlation was found in HCs. Moreover, the increased expression of human orthologues of the IOI genes in ONCs was significantly correlated with the OB volume reduction in FEP, but not in HCs. Together, our study implies a potential mechanism of the OE-OB pathology in patients with psychotic disorders (schizophrenia and related disorders). We hope that this mechanism may have a cross-disease implication, including COVID-19-elicited mental conditions that include smell deficits.

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Fig. 1: Structural alterations in the OB of the IOI mice.
Fig. 2: Behavioral deficits in the IOI mice.
Fig. 3: Volumetric alterations in OB in FEP patients.
Fig. 4: Correlation between OB volume and expression profiles in ONCs.

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Data availability

The RNA-seq data and analysis scripts have been made publicly accessible on GitHub: https://github.com/KunYang99/Inflammation_ONC.

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Acknowledgements

This study is supported by the National Institutes of Mental Health Grants MH-092443 (to AS), MH-094268 (to AS, AK), MH-105660 (to AS), MH-107730 (to AS), and MH-128765 (to AK); foundation grants from Stanley (to AS), RUSK/S-R (to AS), a NARSAD young investigator award from the Brain and Behavior Research Foundation (to AS, KY), NS-108452 (to JH, VK), AG-064093 (to JH, VK), DA-041208 (to AK), AG-065168 (to AK), DC-016106 (to AL), AI-132590 (to AL), DC-006213 (to MM), Kanae (YH), and Mitsui Sumitomo Insurance Welfare Foundation (YH). Figures 1A and 2B were created with a graphical software provided by Biorender.com. The authors wish to extend their gratitude to the participants in the current study. The authors thank Dr. Yu Miyahara and Ms. Vesna Tran for assisting mouse study, thank Ms. Yukiko Lema for research management and manuscript organization, and thank Dr. Melissa A Landek-Salgado for scientific and English editions.

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  1. These authors contributed equally: Kun Yang, Yuto Hasegawa.

Authors and Affiliations

  1. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Kun Yang, Yuto Hasegawa, Semra Etyemez, Neal Prasad, Lauren Duvall, Koko Ishizuka, Vidyulata Kamath, Atsushi Kamiya & Akira Sawa

  2. Department of Neuroscience, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Janardhan P. Bhattarai, Yingqi Wang, Yun-Feng Zhang & Minghong Ma

  3. Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Jun Hua

  4. F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA

    Jun Hua & Adrian Paez

  5. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Milan Dower & Akira Sawa

  6. Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Amy Smith & Andrew P. Lane

  7. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Akira Sawa

  8. Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Akira Sawa

  9. Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Akira Sawa

  10. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Akira Sawa

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Contributions

The current research was designed by AS (Sawa). The analytic pipeline was designed by KY. The preclinical study regarding anatomical assessment and mouse behavioral test was designed by AK and carried out by YH. The preclinical study regarding patch clamp recording was designed by MM and carried out by JPB with the assistance of YW and YFZ. Both clinical and preclinical data were analyzed by KY, with the assistance of YH, JPB, MD, and SE. The anatomical assessment of the human olfactory bulb was supervised by JH and carried out by NP, LD, and AP. Nasal biopsy was designed and conducted by APL, with the assistance of AS (Smith). The olfactory neuronal cells were enriched from biopsied olfactory epithelium by KI. The clinical data interpretation was guided by AS (Sawa), JH, and VK. The manuscript was drafted by KY, YH, JPB, KI, MM, AK, and AS (Sawa). All authors contributed to the discussion of the results and have approved the final manuscript to be published.

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Correspondence to Atsushi Kamiya or Akira Sawa.

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Yang, K., Hasegawa, Y., Bhattarai, J.P. et al. Inflammation-related pathology in the olfactory epithelium: its impact on the olfactory system in psychotic disorders. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02425-8

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