Neuronal TLR4 signaling enhances AMPA currents and drives posttraumatic epileptogenesis

Summary 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 acquired epilepsies. Here we identify that signaling through an innate immune receptor toll-like receptor 4 (TLR4), in neurons, augments calcium permeable AMPA currents in the hippocampal dentate gyrus after brain injury. Blocking TLR4 signaling in vivo early after brain injury reduced dentate network excitability and seizure susceptibility. TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls. However, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. TLR4 antagonists failed to reduce post-injury seizure susceptibility when treatment was delayed and was less efficacious when AMPA currents were transiently enhanced during TLR4 antagonist treatment. These data identify a direct immune receptor regulation of post-traumatic neuronal excitability which is independent of glia. Moreover, the results demonstrate a causal association between TLR4-dependent early increase in dentate excitability and epileptogenesis. The findings suggest that the mechanisms underlying the aberrant TLR4 mediated increase in CP-AMPA after injury could be identified and selectively targeted to prevent epileptogenesis after traumatic brain injury. Graphical Abstract