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Cronobacter sakazakii Infection in Early Postnatal Rats Impaired Contextual-Associated Learning: a Putative Role of C5a-Mediated NF-κβ and ASK1 Pathways

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Abstract

This study was designed to test whether the Cronobacter sakazakii infection-impaired contextual learning and memory are mediated by the activation of the complement system; subsequent activation of inflammatory signals leads to alternations in serotonin transporter (SERT). To test this, rat pups (postnatal day, PND 15) were treated with either C. sakazakii (107 CFU) or Escherichia coli OP50 (107 CFU) or Luria bertani broth (100 μL) through oral gavage and allowed to stay with their mothers until PND 24. Experimental groups’ rats were allowed to explore (PNDs 31–35) and then trained in contextual learning task (PNDs 36–43). Five days after training, individuals were tested for memory retention (PNDs 49–56). Observed behavioural data showed that C. sakazakii infection impaired contextual-associative learning and memory. Furthermore, our analysis showed that C. sakazakii infection activates complement system complement anaphylatoxin (C5a) (a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1)) and mitogen-activated protein kinase kinase1 (MEKK1). Subsequently, MEKK1 induces pro-inflammatory signals possibly through apoptosis signal-regulating kinase-1 (ASK-1), c-Jun N-terminal kinase (JNK1/3) and protein kinase B gamma (AKT-3). In parallel, activated nuclear factor kappa-light-chain-enhancer B cells (NF-κB) induces interleukin-6 (IL-6) and IFNα-1, which may alter the level of serotonin transporter (SERT). Observed results suggest that impaired contextual learning and memory could be correlated with C5a-mediated NF-κβ and ASK1 pathways.

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Data Availability

All datasets generated for this study are included in the manuscript.

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Acknowledgements

We thank the reviewers for their comments to improve the manuscript.

Funding

This study was financially supported by Department of Biotechnology, Government of India, through major project (BT/PR17367/MED/122/44/2016) to KER and KB, and Department of Animal Science Instrumentation facility supported by UGC-SAP-DRS-II and DST-FIST.

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  1. Behavioural Neuroscience Laboratory, Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli, 620024, India

    Ponnusamy Vinay, Christopher Karen & Koilmani Emmanuvel Rajan

  2. Department of Biotechnology, Alagappa University, Karaikudi, 630003, India

    Krishnaswamy Balamurugan

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  1. Ponnusamy Vinay
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Supplementary 1

Working model: Overview of the inflammatory signalling pathway that possibly alter the synaptic plasticity, learning and memory. Cronobacter sakazakii infection induced activation of Tol-like receptors (TLRs)/ pathogen recognition receptors (PRRs) further activate complement system complement anaphylatoxin (C5a). Subsequently, different stimuli activate tiers of protein kinases, which phosphorylate different proteins involving in signalling pathway that regulates/ cause defects in synaptic plasticity, learning and memory depend on the activation of proteins. The molecules marked with asterisk examined in the present study (PNG 975 kb)

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Vinay, P., Karen, C., Balamurugan, K. et al. Cronobacter sakazakii Infection in Early Postnatal Rats Impaired Contextual-Associated Learning: a Putative Role of C5a-Mediated NF-κβ and ASK1 Pathways. J Mol Neurosci 71, 28–41 (2021). https://doi.org/10.1007/s12031-020-01622-8

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