A Novel NLRP3 Inhibitor AMS ‐17 Rescues Deficits in Long‐Term Potentiation Following Mild Traumatic Brain Injury in Adult C57Bl /6 Mice

Traumatic brain injury (TBI) is a leading cause of long-term disability, with limited effective treatment options. A key factor of TBI pathophysiology is neuroinflammation, which can involve the activation of the nucleotide-binding domain leucine-rich repeat protein 3 (NLRP3) inflammasome. Aberrant inflammation following injury has the ability to reduce the capacity to induce long-term changes in synaptic plasticity, a leading mechanism for the development of learning and memory deficits following injury. This study investigated the potential of a novel NLRP3 inhibitor, AMS-17, to mitigate synaptic plasticity deficits following mild TBI (mTBI) in mice. Adult C57Bl/6 mice were subjected to mTBI or a sham injury, and hippocampal slices were then prepared for field electrophysiological recordings in the medial perforant pathway of the dentate gyrus. We found that mTBI induced deficits in long-term potentiation that were not immediate at 2 h post-injury but developed by 3 days post-injury. We next incubated slices in AMS-17 or a control solution prior to electrophysiological recordings. Here we found that incubation with AMS-17 rescued these LTP deficits, bringing them to levels observed in sham-injured controls. Importantly, AMS-17 did not affect the capacity to induce LTP in sham-injured mice. These findings suggest that targeting the NLRP3 inflammasome may offer a promising therapeutic strategy to reduce learning and memory impairments following mTBI. Further studies are needed to determine the optimal therapeutic window and long-term efficacy of AMS-17 in mTBI.