The effects of MyD88 deficiency on exploratory activity, anxiety, motor coordination, and spatial learning in C57BL/6 and APPswe/PS1dE9 mice

Abstract

Toll-like receptors (TLRs) are a family of pattern-recognition receptors in innate immunity and provide a first line defense against pathogens and tissue injuries. In addition to important roles in infection, inflammation, and immune diseases, recent studies show that TLR signaling is involved in modulation of learning, memory, mood, and neurogenesis. Because MyD88 is essential for the downstream signaling of all TLRs, except TLR3, we investigated the effects of MyD88 deficiency (MyD88-/-) on behavioral functions in mice. Additionally, we recently demonstrated that a mouse model of Alzheimer's disease (AD) deficient for MyD88 had decreases in Aβ deposits and soluble Aβ in the brain as compared with MyD88 sufficient AD mouse models. Because accumulation of Aβ in the brain is postulated to be a causal event leading to cognitive deficits in AD, we investigated the effects of MyD88 deficiency on behavioral functions in the AD mouse model at 10 months of age. MyD88 deficient mice showed more anxiety in the elevated plus-maze. In the motor coordination tests, MyD88 deficient mice remained on a beam and a bar for a longer time, but with slower initial movement on the bar. In the Morris water maze test, MyD88 deficiency appeared to improve spatial learning irrespective of the transgene. Our findings suggest that the MyD88-dependent pathway contributes to behavioral functions in an AD mouse model and its control group.

Figure 1

Effects of MyD88 deficiency on APP or WT mice on exploration in the open-field. A-C, Distance travelled at the periphery (A) and center (B) of the open-field as well as the center/total time ratio (C) are shown as means ± SEM in 5 min sessions for 3 days. The center/total time rations of APP MyD88-/- mice are similar to those of APP mice (C). D-F, Percent time spent resting (D), moving slow (E), and moving fast (F) in the open-field are shown as means ± SEM in 5-min sessions for 3 days.

Figure 2

Effects of MyD88 deficiency on APP or WT mice on the rotorod. Latencies before falling (means ± SEM) from the accelerating rotorod observed in the 4 experimental mouse groups in 4-trial sessions for 3 days. * P < 0.05: APP groups vs. non-APP groups.

Figure 3

Effects of MyD88 deficiency on APP or WT mice on Morris water maze. Total cumulated scores per day for path length (cm) (A) and escape latencies (s) (B). Means ± SEM are shown during acquisition of the hidden platform task. MyD88 deficiency improved performance of APP and WT mice. (C) The probe trial of the Morris water maze. Percent of time spent in the target quadrant in which the hidden platform was previously placed. The dashed line indicates the chance level (25%). All groups spent significantly longer than chance in the target quadrant (P < 0.05) and no difference was found in any group. * P < 0.05: MyD88 deficient groups vs. MyD88 sufficient groups, ** P < 0.01: APP groups vs. non-APP groups.