%0 Journal Article %A Yu Liu %A Samuel S. McAfee %A Natalie M. Guley %A Nobel Del Mar %A Wei Bu %A Scott A. Heldt %A Marcia G. Honig %A Bob M. Moore II %A Anton Reiner %A Detlef H. Heck %T Abnormalities in Dynamic Brain Activity Caused by Mild Traumatic Brain Injury Are Partially Rescued by the Cannabinoid Type-2 Receptor Inverse Agonist SMM-189 %D 2017 %R 10.1523/ENEURO.0387-16.2017 %J eneuro %P ENEURO.0387-16.2017 %X Mild traumatic brain injury (mTBI) can cause severe long-term cognitive and emotional deficits, including impaired memory, depression and persevering fear, but the neuropathological basis of these deficits is uncertain. As medial prefrontal cortex (mPFC) and hippocampus play important roles in memory and emotion, we used multi-site, multi-electrode recordings of oscillatory neuronal activity in local field potentials (LFPs) in awake, head-fixed mice to determine if the functioning of these regions was abnormal after mTBI, using a closed-skull focal cranial blast model. We evaluated mPFC, hippocampus CA1, and primary somatosensory/visual cortical areas (S1/V1). Although mTBI did not alter the power of oscillations, it did cause increased coherence of theta (4-10Hz) and beta (10-30Hz) oscillations within mPFC and S1/V1, reduced CA1 sharp-wave ripple-evoked LFP activity in mPFC, downshifted sharp-wave ripple frequencies in CA1, and enhanced theta-gamma phase-amplitude coupling within mPFC. These abnormalities might be linked to the impaired memory, depression and persevering fear seen after mTBI.Treatment with the cannabinoid type-2 (CB2) receptor inverse agonist SMM-189 has been shown to mitigate functional deficits and neuronal injury after mTBI in mice. We found that SMM-189 also reversed most of the observed neurophysiological abnormalities. This neurophysiological rescue is likely to stem from the previously reported reduction in neuron loss and/or the preservation of neuronal function and connectivity resulting from SMM-189 treatment, which appears to stem from the biasing of microglia from the pro-inflammatory M1 state to the pro-healing M2 state by SMM-189.Significance Statement Using a mouse model, we show that mild traumatic brain injury (mTBI) caused significant abnormalities in oscillatory neuronal activity patterns in CA1 of hippocampus and medial prefrontal cortex, two structures strongly implicated in cognitive and emotional processes. The cannabinoid type-2 receptor specific inverse agonist SMM-189, which has been shown to reverse behavioral deficits and neuronal loss in the present model of mTBI, also rescued most of the electrophysiological deficits. Taken together, our current and previously published studies suggest that use of CB2 receptor inverse agonists such as SMM-189, which appear to act by biasing microglia from the pro-inflammatory M1 state to the pro-healing M2 state, may be a promising therapeutic approach for mTBI. %U https://www.eneuro.org/content/eneuro/early/2017/07/24/ENEURO.0387-16.2017.full.pdf