Evidence for a Developmental Role for TLR4 in Learning and Memory

Toll-like receptors (TLRs) play essential roles in innate immunity and increasing evidence indicates that these receptors are expressed in neurons, astrocytes and microglia in the brain where they mediate responses to infection, stress and injury. Very little is known about the roles of TLRs in cognition. To test the hypothesis that TLR4 has a role in hippocampus-dependent spatial learning and memory, we used mice deficient for TLR4 and mice receiving chronic TLR4 antagonist infusion to the lateral ventricles in the brain. We found that developmental TLR4 deficiency enhances spatial reference memory acquisition and memory retention, impairs contextual fear-learning and enhances motor functions, traits that were correlated with CREB up-regulation in the hippocampus. TLR4 antagonist infusion into the cerebral ventricles of adult mice did not affect cognitive behavior, but instead affected anxiety responses. Our findings indicate a developmental role for TLR4 in shaping spatial reference memory, and fear learning and memory. Moreover, we show that central TLR4 inhibition using a TLR4 antagonist has no discernible physiological role in regulating spatial and contextual hippocampus-dependent cognitive behavior.Toll样受体（Toll-like receptors，TLRs）在固有免疫中发挥关键作用，越来越多的证据表明，此类受体在大脑的神经元、星形胶质细胞与小胶质细胞中表达，并介导机体对感染、应激与损伤的应答。目前人们对TLRs在认知过程中的功能尚知之甚少。为验证TLR4参与海马依赖性空间学习与记忆这一假说，我们分别采用TLR4缺陷型小鼠，以及向大脑侧脑室慢性输注TLR4拮抗剂的小鼠开展实验。研究发现，发育阶段的TLR4缺陷可增强空间参考记忆的获取与巩固能力，损害情境恐惧条件反射，并提升运动功能，这些表型与海马内环腺苷酸应答元件结合蛋白（cAMP response element-binding protein，CREB）的上调表达相关。向成年小鼠脑室输注TLR4拮抗剂并不会影响其认知行为，但会改变其焦虑反应。本研究结果表明，TLR4在发育阶段可调控空间参考记忆以及恐惧学习与记忆过程。此外，我们还证实，通过TLR4拮抗剂实现中枢TLR4抑制，对调节海马依赖性空间与情境认知行为并无显著生理作用。