Project Summary This proposal seeks to better understand the contribution of cortical inhibitory interneuron subtypes to network dysfunction after mild traumatic brain injury (mTBI) utilizing a well controlled and characterized mouse model, the central fluid percussion injury. Our group has identified significant and differential dysfunction in neocortical interneuron subtypes after mTBI in this model. Parvalbumin interneurons (PV) modulate gamma oscillations recorded from EEG that is critical for sensory perception. The PV are particularly vulnerable after injury, with 10% being axotomized and the output from PV to local pyramidal neurons being significantly reduced. In contrast somatostatin-containing interneurons (SOM) show little axotomy and have an increased output onto local pyramidal neurons. In other disease models the link between the ratio of PV:SOM and altered gamma levels has been well established. We hypothesize that injury also alters this ratio and that alteration underlies the increase in resting gamma and the decrease in evoked gamma that we and others have observed. We will test that here using chemogenetics and mutant mice with altered PV:SOM ratios. In addition we will test the link of that altered gamma to an increased sensitivity to touch and lowered pain threshold. We further hypothesize that the reason PV are vulnerable is due to the activation of microglia which subsequently degrade the perineuronal nets (PNN) that normally surround the PV. Once the PNN are removed PV function is likely reduced due to reactive oxygen species. Each aspect of these hypotheses will be tested by depleting microglia and by treating the oxidative stress with N-Acetylcysteine. Outcome measures will include the power of the gamma recorded from EEG, pain threshold via von Frey filaments, whisker nuisance test score, the percent of axotomized PV and SOM interneurons, the intracellularly recorded function of the PV and SOM and the level of output from PV and SOM. These studies will determine if this cellular dysfunction underlies the abnormal network function and altered cognition after mTBI.