Opposing actions of hippocampus TNFα receptors on limbic seizure susceptibility

Exp Neurol. 2013 Sep:247:429-37. doi: 10.1016/j.expneurol.2013.01.011. Epub 2013 Jan 16.


Resected epileptic tissues exhibit elements of chronic neuroinflammation that include elevated TNFα and increased TNFα receptor activation, but the seizure related consequences of chronic TNFα expression remain unknown. Twenty four hours after acute limbic seizures the rat hippocampus exhibited a rapid upregulation of TNFR1, but a simultaneous downregulation of TNFR2. These limbic seizures also evoked significant increases in measures of neuroinflammation and caused significant neuronal cell death in both the hilus and CA3 of the hippocampus. In order to mimic a state of chronic TNFα exposure, adeno-associated viral vectors were packaged with a TNF receptor 1 (TNFR1) specific agonist, human TNFα, or a TNF receptor 1/2 agonist, rat TNFα. Subsequently, chronic hippocampal overexpression of either TNFR ligand caused microglial activation and blood-brain barrier compromise, a pattern similar to limbic seizure-induced neuroinflammation. However, no evidence was found for neuronal cell death or spontaneous seizure activity. Thus, chronic, in vivo TNFα expression and the subsequent neuroinflammation alone did not cause cell death or elicit seizure activity. In contrast, chronic hippocampal activation of TNFR1 alone significantly increased limbic seizure sensitivity in both amygdala kainic acid and electrical amygdala kindling models, while chronic activation of both TNFR1 and TNFR2 significantly attenuated the amygdala kindling rate. With regard to endogenous TNFα, chronic hippocampal expression of a TNFα decoy receptor significantly reduced seizure-induced cell death in the hippocampus, but did not alter seizure susceptibility. These findings suggest that blockade of endogenous TNFα could attenuate seizure related neuropathology, while selective activation of TNFR2 could exert beneficial therapeutic effects on in vivo seizure sensitivity.

Keywords: AAV; Adeno-associated virus; Epilepsy; Neuroimmune; Neuropathology; Seizures; TNF receptors; TNF-alpha; TNF-α; TNFR; adeno-associated virus; tumor necrosis factor receptor; tumor necrosis factor-alpha.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • CD11b Antigen
  • Cell Line, Transformed
  • Gene Expression Regulation / physiology
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / metabolism*
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Kindling, Neurologic
  • Limbic System / pathology*
  • Male
  • Nerve Tissue Proteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Seizures / pathology*
  • Time Factors
  • Transfection
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / metabolism*


  • CD11b Antigen
  • Histocompatibility Antigens Class II
  • Nerve Tissue Proteins
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Green Fluorescent Proteins