Young and aged TLR4 deficient mice show sex-dependent enhancements in spatial memory and alterations in interleukin-1 related genes

Toll-like receptor-4 (TLR4) is a transmembrane receptor that initiates an immune response following a bacterial infection or host derived molecules associated with cellular distress. Beyond triggering inflammation, TLR4 has been implicated in modulating behavioral and cognitive processes in a physiologically normal state, as young adult TLR4 deficient mice show learning enhancements in select tasks. Currently unknown is whether these benefits are present in both sexes and persist with aging. The present study evaluated spatial memory, anxiety like behavior, and central levels of pro- and anti-inflammatory molecules in young (4-5 months) and aged (18-19 months) TLR4 deficient (TLR4-/-) and wild-type (WT) male and female mice. Results confirmed that TLR4-/- mice show enhanced spatial memory compared to WT mice. These effects were age- and sex-specific, as memory retention was superior in the TLR4-/- young males and aged females. While TLR4-/- mice showed age-related changes in behavior, these changes were attenuated relative to aged WT mice. Further, aged TLR4-/- mice showed differential expression of molecules involved in interleukin (IL)-1 signaling in the hippocampus. For instance, aged TLR4-/- females showed heightened expression of IL-1 receptor antagonist (IL-1ra) and the IL-1 accessory proteins AcP and AcPb. Collectively, these data provide the initial evidence that TLR4 deficiency enhances cognitive function and modulates the inflammatory profile of the hippocampus in a sex- and age-dependent manner.