Abnormalities in dynamic brain activity caused by mild traumatic brain injury are partially rescued by the cannabinoid type-2 receptor inverse agonist SMM-189

Yu Liu, Samuel S. McAfee, Natalie M. Guley, Nobel Del Mar, Wei Bu, Scott A. Heldt, Marcia G. Honig, Bob M. Moore, Anton Reiner, Detlef H. Heck

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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 θ (4-10 Hz) and α (10-30 Hz) oscillations within mPFC and S1/V1, reduced CA1 sharp-wave ripple (SWR)-evoked LFP activity in mPFC, downshifted SWR frequencies in CA1, and enhanced θ-γ phase-amplitude coupling (PAC) 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 proinflammatory M1 state to the prohealing M2 state by SMM-189.

Original languageEnglish (US)
Article numbere0387-16.2017
JournaleNeuro
Volume4
Issue number4
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by funding from the University of Tennessee Health Science Center (UTHSC) Department of Anatomy and Neurobiology, the UTHSC Neuroscience Institute and National Institutes of Health (NIH) Grant NS091752 (to D.H.H.), The Office of the Dean of the College of Medicine at UTHSC (A.R.), The Methodist Hospitals Endowed Professorship in Neuroscience (A.R.), the NIH Grant NS-081370 (to A.R.), and the College of Pharmacy at UTHSC (B.M.M.).

Publisher Copyright:
© 2017 Liu et al.

Keywords

  • Cannabinoid type 2 receptor
  • Coherence
  • Mild traumatic brain injury
  • Neuronal oscillations
  • Phase amplitude coupling

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