Compared with wild-type mice, Tlr3−/− mice showed similar learning but improved memory performance in a Morris water maze test. In addition, Tlr3−/− mice were better than wild-type mice at finding the platform in the maze when it was moved every day, suggesting superior working memory. During hippocampus-dependent contextual fear conditioning, Tlr3−/− mice froze more than wild-type mice and showed slower extinction of contextual memory. Next, the authors directly activated TLR3 in the CNS by infusion of polyinosinic–polycytidylic acid into the lateral ventricle of wild-type mice and showed that this impaired working memory performance in the Morris water maze test. These results indicate that TLR3 negatively regulates hippocampus-dependent working memory.
Are these memory retention improvements in Tlr3−/− mice associated with structural and cellular signalling changes in the hippocampus? The authors found that the dentate gyrus and CA1 regions of the hippocampus, both of which normally express TLR3, were enlarged in the Tlr3−/− mice. Furthermore, neurogenesis was increased in the dentate gyrus of adult Tlr3−/− mice, and levels of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GluA1, which contributes to hippocampus-dependent memory, were increased in CA1 neurons. The canonical TLR3 signalling pathway was not altered in the hippocampus of Tlr3−/− mice, consistent with its direct responsiveness to invading pathogens and tissue injury. Instead, expression and phosphorylation of extracellular signal-regulated kinase 1 (ERK1), ERK2 and cyclic AMP-responsive element-binding protein (CREB) were increased, suggesting that TLR3 has a role in inhibiting other pathways that are associated with synaptic plasticity.
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