Developmental TLR4 deficiency, but not pharmacological TLR4 antagonism, enhances retention of spatial reference memory.

<p>(<b>A</b>) TLR4^−/− (n = 19) and TLR4^+/+ (n = 24) mice were tested in probe trials at 24, 48, 72 and 96 hours following training for retention of spatial reference memory. Tests were done after all experimental groups exhibited loss of memory of the platform location. Mean distance from the platform was measured and used to indicate efficiency in locating the hidden platform. TLR4^−/− mice showed shorter mean distance from the platform at 24 and 48 hours after training compared with TLR4^+/+ mice, indicating a more accurate swim toward the platform quadrant (<b>B</b>) Mice (C57BL/6) were implanted with an osmotic pump containing either aCSF (n = 10) or a TLR4 antagonist (n = 10). The pump was connected via tubing to a cannula, which was positioned to the lateral ventricle. Following training in the MWM task, mice were tested in probe trials at 24 and 48 hours following training for retention of spatial reference memory. Both experimental groups exhibited similar performance during probe trials, as measured by mean distance from the platform.</p

Pharmacological TLR4 inhibition does not affect fear-learning and memory.

<p>(<b>A</b>) aCSF infused mice (n = 10) show similar association curves in the fear-conditioning paradigm compared with TLR4 antagonist infused mice (n = 10). (<b>B</b>) aCSF infused mice (n = 10) show similar freezing levels in the fear-conditioning paradigm compared with TLR4 antagonist infused mice (n = 10). (<b>C</b>) Average freezing during contextual fear. (<b>D</b>) aCSF infused mice (n = 10) show similar freezing in the fear-conditioning paradigm compared with TLR4 antagonist infused mice (n = 10) in the presence of tone.</p

CREB and p-CREB are upregulated in the hippocampus of TLR4^−/− mice.

<p>Brains from TLR4^+/+ (n = 8) and TLR4^−/− (n = 8) mice were dissected and hippocampi were removed. Tissues were then lysed, electrophoresed and immunoblotted against GluR1, CREB, ERK and their phosphorylated forms. Representative blots demonstrate that levels of CREB and pCREB were upregulated in TLR4^−/− mice compared to TLR4^+/+ mice, whereas GluR1, ERK and their phosphorylated forms were not changed. * p<0.05.</p

Developmental TLR4 deficiency impairs fear-learning and memory.

<p>(<b>A</b>) TLR4^−/− (n = 19) mice show impaired association curves in the fear-conditioning paradigm compared with TLR4^+/+ (n = 24) mice. (<b>B</b>) TLR4^−/− mice exhibit significantly impaired hippocampus dependent contextual fear compared to TLR4^+/+ mice, as measured by time freezing during 5 minutes of exposure to the original context. (<b>C</b>) Average freezing during contextual fear. (<b>D</b>) TLR4^−/− mice exhibit reduced freezing compared with TLR4^+/+ mice in the presence of tone, indicating impaired fear response.</p