Blocking Tumor Necrosis Factor-Alpha Expression Prevents Blast-Induced Excitatory/Inhibitory Synaptic Imbalance and Parvalbumin-Positive Interneuron Loss in the Hippocampus

Weihua Wang, Alexander K. Zinsmaier, Ethan Firestone, Ruizhu Lin, Tatiana A. Yatskievych, Sungchil Yang, Jinsheng Zhang, Shaowen Bao

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Traumatic brain injury (TBI) is a major cause of neurological disorder and death in civilian and military populations. It comprises two components-direct injury from the traumatic impact and secondary injury from ensuing neural inflammatory responses. Blocking tumor necrosis factor-alpha (TNF-α), a central regulator of neural inflammation, has been shown to improve functional recovery after TBI. However, the mechanisms underlying those therapeutic effects are still poorly understood. Here, we examined effects of 3,6'-dithiothalidomide (dTT), a potentially therapeutic TNF-α inhibitor, in mice with blast-induced TBI. We found that blast exposure resulted in elevated expression of TNF-α, activation of microglial cells, enhanced excitatory synaptic transmission, reduced inhibitory synaptic transmission, and a loss of parvalbumin-positive (PV+) inhibitory interneurons. Administration of dTT for 5 days after the blast exposure completely suppressed blast-induced increases in TNF-α transcription, largely reversed blasted-induced synaptic changes, and prevented PV+ neuron loss. However, blocking TNF-α expression by dTT failed to mitigate blast-induced microglial activation in the hippocampus, as evidenced by their non-ramified morphology. These results indicate that TNF-α plays a major role in modulating neuronal functions in blast-induced TBI and that it is a potential target for treatment of TBI-related brain disorders.

Original languageEnglish (US)
Pages (from-to)2306-2316
Number of pages11
JournalJournal of Neurotrauma
Volume35
Issue number19
DOIs
StatePublished - Oct 1 2018

Keywords

  • TNF-α
  • blast exposure
  • hippocampus
  • synaptic transmission
  • traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology

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