Department of Pharmacology, Physiology, and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ.
Department of Molecular, Cell, and Systems Biology, University of California Riverside, Riverside, CA.
Ann Neurol. 2020 Apr;87(4):497-515. doi: 10.1002/ana.25698. Epub 2020 Feb 24.
Traumatic brain injury is a major risk factor for acquired epilepsies, and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor Toll-like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury.
Slice and in vivo electrophysiology and Western blots were conducted in rats subject to fluid percussion brain injury or sham injury.
The studies identify that TLR4 signaling in neurons augments dentate granule cell calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (CP-AMPAR) currents after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce postinjury seizure susceptibility. Furthermore, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls.
These findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post-traumatic neuronal excitability. Moreover, the TLR4-dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4-mediated increase in CP-AMPAR signaling after injury may prevent epileptogenesis after brain trauma. ANN NEUROL 2020;87:497-515.
创伤性脑损伤是获得性癫痫的主要危险因素，了解早期病理生理学的机制可能产生可行的治疗靶点。越来越多的证据表明炎症信号在调节神经元兴奋性和促进癫痫发生中起作用。在这里，我们研究了先天免疫受体 Toll 样受体 4（TLR4）对脑损伤后海马齿状回兴奋性和癫痫发生的影响。
对接受流体冲击脑损伤或假损伤的大鼠进行切片和体内电生理学及 Western blot 分析。
研究表明，TLR4 信号在神经元中增强了脑损伤后齿状回颗粒细胞钙通透性 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体（CP-AMPAR）电流。脑损伤后体内短暂阻断 TLR4 信号可降低齿状回网络兴奋性和癫痫易感性。然而，当损伤后阻断 TLR4 信号延迟时，这种治疗方法未能降低损伤后癫痫易感性。此外，当 TLR4 信号阻断时，CP-AMPAR 信号下游靶点的 AMPAR 电流短暂增强时，对限制癫痫易感性的作用较小。矛盾的是，TLR4 信号阻断在未受伤的对照组中增强了网络兴奋性和癫痫易感性。尽管对癫痫易感性的影响不同，但 TLR4 拮抗剂抑制损伤后细胞炎症反应，而不影响假对照。
这些发现表明，免疫受体 TLR4 独立于神经胶质细胞，直接调节创伤后神经元兴奋性。此外，TLR4 依赖性齿状回兴奋性的早期增加与癫痫发生有关。鉴定和选择性靶向损伤后异常 TLR4 介导的 CP-AMPAR 信号增加的机制可能预防创伤性脑损伤后的癫痫发生。神经病学年鉴 2020；87：497-515。
