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Influenza A Virus PB1-F2 Induces Affective Disorder by Interfering Synaptic Plasticity in Hippocampal Dentate Gyrus

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Abstract

Influenza A virus (IAV) infection, which leads to millions of new cases annually, affects many tissues and organs of the human body, including the central nervous system (CNS). The incidence of affective disorders has increased after the flu pandemic; however, the potential mechanism has not been elucidated. PB1-F2, a key virulence molecule of various influenza virus strains, has been shown to inhibit cell proliferation and induce host inflammation; however, its role in the CNS has not been studied. In this study, we constructed and injected PB1-F2 into the hippocampal dentate gyrus (DG), a region closely associated with newborn neurons and neural development, to evaluate its influence on negative affective behaviors and learning performance in mice. We observed anxiety- and depression-like behaviors, but not learning impairment, in mice injected with PB1-F2. Furthermore, pull-down and mass spectrometry analyses identified several potential PB1-F2 binding proteins, and enrichment analysis suggested that the most affected function was neural development. Morphological and western blot studies revealed that PB1-F2 inhibited cell proliferation and oligodendrocyte development, impaired myelin formation, and interfered with synaptic plasticity in DG. Taken together, our results demonstrated that PB1-F2 induces affective disorders by inhibiting oligodendrocyte development and regulating synaptic plasticity in the DG after IAV infection, which lays the foundation for developing future cures of affective disorders after IAV infection.

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Data Availability

The authors will provide the data under a reasonable request.

Abbreviations

IAV:

Influenza A virus

PB1-F2:

protein 1-frame 2

CNS:

central nervous system

DG:

dentate gyrus

IL-1β:

interleukin-1β

IL-6:

interleukin-6

TNF-α:

tumor necrosis factor-α

LTP:

long-term potentiation

ANT3:

adenine nucleotide translocator 3

VDAC1:

voltage-dependent anion channel 1

NLRX1:

nucleotide-binding oligomerization domain-like receptor X1

TUFM:

Tu translation elongation factor, mitochondrial

LC3B:

microtubule associated protein 1 light chain 3 beta

NLRP3:

NLR family pyrin domain containing 3

PDGFRα:

platelet derived growth factor receptor alpha

OLIG2:

oligodendrocyte lineage transcription factor 2

GAP43:

growth associated protein-43

SOX10:

SRY-box containing gene10

MAP2:

microtubule associated protein-2

NMDA:

N-methyl-D-aspartate

AMPA:

alberta magazine publishers association

BDNF:

brain derived nerve factor

CaMKII:

calmodulin dependent protein kinase II

PSD95:

postsynaptic density-95

GluN2A:

glutamate receptor ionotropic, NMDA 2A

GluN2B :

glutamate receptor ionotropic, NMDA 2B

GluA1:

glutamate receptor ionotropic, AMPA 1

GluA2:

glutamate receptor ionotropic, AMPA 2

MCT1:

monocarboxylate transporter 1

OPCs:

oligodendrocyte progenitor cells

OLs:

mature oligodendrocytes

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Acknowledgements

We thank the National Natural Science Foundation of China and the Shaanxi Province Key Industry Innovation Chain Project for funding.

Funding

This work was supported by the National Natural Science Foundation of China (Grant numbers 31972902, 81771469, and 31800887) and partially supported by the Shaanxi Province Key Industry Innovation Chain Project (Grant number 2023-ZDLSF-59).

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Author notes

  1. Saiying Wang, Haijun Zhang, Rui Liu, and Peijun Han contributed equally to this study.

Authors and Affiliations

  1. Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi’an, China

    Saiying Wang, Qi Yang, Caiyan Cheng, Yue Chen, Zheng Rong, Chang Su, Fei Li, Minggao Zhao & Le Yang

  2. Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Key Laboratory of Aerospace Medicine of Ministry of Education, Air Force Medical University, Xi’an, 710032, China

    Haijun Zhang

  3. Department of Rehabilitation, Tangdu Hospital, Air Force Medical University, Xi’an, China

    Rui Liu

  4. Department of Aerospace Hygiene, School of Aerospace Medicine, Air Force Medical University, Xi’an, China

    Peijun Han

  5. Institute of Medical Research, Northwestern Polytechnical University, Xi’an, China

    Gaofei Wei

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  1. Saiying Wang
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Contributions

Le Yang, Rui Liu, and Peijun Han conceived and designed this study. Le Yang, Minggao Zhao and Gaofei Wei supervised this study. Saiying Wang, Haijun Zhang, Caiyan Cheng, Yue Chen, Zheng Rong, Fei Li, and Chang Su performed data collection and analysis. Saiying Wang and Le Yang drafted the manuscript. Qi Yang revised the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Le Yang.

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All experimental procedures were approved by the Ethics Committee of the Fourth Military Medical University (Approval No. KY20193145) in full compliance with the ethical guidelines of the National Institutes of Health for the care and use of laboratory animals.

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Wang, S., Zhang, H., Liu, R. et al. Influenza A Virus PB1-F2 Induces Affective Disorder by Interfering Synaptic Plasticity in Hippocampal Dentate Gyrus. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04107-6

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