Systemic Inflammation and Neuronal Hyperexcitability: Deciphering Cellular Neuropathology of Sickness Behaviour.

Toll-like receptors (TLRs) participate in the response to infection, stress, and injury by initiating an innate immune response. In addition, these receptors are expressed in many neural cell types and under physiological conditions are implicated in modulating cognitive function and neural plasticity in the adult and aged brain. Knockout of the Toll-like receptor 4 (TLR4) subtype enhances spatial memory and adult hippocampal neurogenesis through increasing proliferation and neuronal differentiation. Currently unknown is whether pharmacological inhibition of TLR4 produces similar enhancements in cognitive function and cell proliferation. The present study evaluated water maze performance, cytokine expression, and cell proliferation in the hippocampus of young and aged male and female C57BL6/J mice following treatment with the TLR4 antagonist, TAK-242. Further, alterations in the response to an acute stressor were evaluated in TAK-242-treated mice. Results showed that TAK-242 selectively enhanced spatial learning and memory in young females. Additionally, TAK-242 treatment reduced thigmotaxis in the water maze and lowered corticosterone levels following acute stress in females. TAK-242 decreased hippocampal interleukin (IL)-1β expression but had no effect on IL-6 or tumor necrosis factor-α (TNFα). Aged mice showed decreased cell proliferation compared to young mice, but TAK-242 administration had minimal effects on estimated Ki67 positive cell numbers. Findings indicate that pharmacological inhibition of TLR4 improves cognitive function in young females likely through attenuating stress reactivity.