TAK-242 has sex-dependent effects on the acquisition of two-way active avoidance conditioning

Toll-like receptor-4 (TLR4) is an immune receptor that influences cognitive and neural plasticity processes under physiological conditions. For instance, pharmacological inhibition of TLR4 selectively enhances spatial learning and memory in females. Whether these sex-dependent changes extend to other cognitive paradigms is presently unclear. The current study evaluated sex differences in associative learning following repeated administration of the TLR4 antagonist, TAK-242. Adult male and female C57BL/6 J mice were trained in a two-way active avoidance conditioning task after receiving TAK-242 or vehicle. The TLR4 antagonist produced sex-specific effects on acquisition, with TAK-242-treated females performing more avoidance responses, while producing no significant effects in males. TAK-242 also selectively increased hippocampal Wnt3a expression in females. Collectively, these findings demonstrate sex-dependent behavioral effects of TAK-242 administration and identify hippocampal Wnt3a as a potential contributor that warrants further investigation.