Reduced Reelin Expression Induces Memory Deficits through Dab-1/ NMDAR Signaling Pathway: Cronobacter sakazakii Infection in a Rat Model of Experimental Meningitis.

The purpose of this study was to examine whether the Cronobacter sakazakii infection-induced inflammation alters the Reelin signaling pathway that is involved in learning and memory. To test this, postnatal day (PND)-15 rat pups were either treated with Luria Bertani broth/Escherichia coli OP50/C. sakazakii through oral gavage or maintained as control and allowed to stay with their mothers until PND-24. Experimental groups' rats were subjected to long-term novel object recognition test during their adolescent age PND-30-32. Observed behavioral data showed that C. sakazakii infection causes a deficit in recognition of novel objects from known objects. Further, our analysis showed that C. sakazakii infection-mediated inflammation decreases the Reelin expression by proteolytic cleavage and alters its receptor apolipoprotein E-receptor (ApoER)-2 splice variants ApoER2 (ex19) and ApoER2 (Δ). Subsequently, downregulated Reelin alters the phosphorylation of disabled adapter protein (Dab)-1 and leads to differential expression of N-methyl-D-aspartate (NMDA) receptor subunits 2A and 2B. Further, the NMDA receptor influences the expression of postsynaptic density (PSD)-95 protein and brain-derived neurotrophic factor (BDNF). Observed results suggest a deficit in recognition of novel objects possibly due to the alternation in Reelin signaling pathway.

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

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-κß and ASK1 pathways.