Microglia depletion improves hippocampal circuit function after mild traumatic brain injury in male mice.

Abstract

Traumatic brain injury (TBI) affects over 69 million people every year, and mild traumatic brain injury (mTBI) accounts for 70-90 % of cases. TBI has two components: i) primary injury - direct damage to the tissue from the mechanical impact and ii) secondary injury - additional or extended damage to the tissue from the ensuing biochemical and physiological processes such as neuroinflammation. Neuroinflammation triggered in part by activated microglia, determines whether the post-injury outcome is recovery or long-term neurodegeneration. Microglia, key components of the neuroinflammatory process, release cytokines such as TNF-α, which affect neuronal activity. Our study investigated the effects of acute microglia depletion on hippocampal neurophysiology in male mice (7-10 days after mTBI), a time window that allows us to target sub-acute microglial responses post-injury. An additional objective of the study was to determine if the pro-inflammatory cytokine TNF-α contributed to the injury-induced network excitability shifts in the hippocampal circuitry. We demonstrate that depleting microglia with PLX-3397 treatment for 7-10 days after mTBI restores network excitability in hippocampal area CA1 and the dentate gyrus (DG). Furthermore, treatments with thalidomide and etanercept show that TNF-α plays a role in altering the network excitability after mTBI. These findings provide new insights into the physiological changes after injury and highlight potential targets for future interventions to specifically address the detrimental effects of chronic inflammation.