RGD Reference Report - Opposing actions of hippocampus TNFalpha receptors on limbic seizure susceptibility. - Rat Genome Database

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Opposing actions of hippocampus TNFalpha receptors on limbic seizure susceptibility.

Authors: Weinberg, MS  Blake, BL  McCown, TJ 
Citation: Weinberg MS, etal., Exp Neurol. 2013 Jan 16. pii: S0014-4886(13)00024-1. doi: 10.1016/j.expneurol.2013.01.011.
RGD ID: 7245573
Pubmed: PMID:23333565   (View Abstract at PubMed)
PMCID: PMC3636186   (View Article at PubMed Central)
DOI: DOI:10.1016/j.expneurol.2013.01.011   (Journal Full-text)

Resected epileptic tissues exhibit elements of chronic neuroinflammation that include elevated TNFalpha and increased TNFalpha receptor activation, but the seizure related consequences of chronic TNFalpha 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 TNFalpha exposure, adeno-associated viral vectors were packaged with a TNF receptor 1 (TNFR1) specific agonist, human TNFalpha, or a TNF receptor 1/2 agonist, rat TNFalpha. 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 TNFalpha 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 TNFalpha, chronic hippocampal expression of a TNFalpha decoy receptor significantly reduced seizure-induced cell death in the hippocampus, but did not alter seizure susceptibility. These findings suggest that blockade of endogenous TNFalpha could attenuate seizure related neuropathology, while selective activation of TNFR2 could exert beneficial therapeutic effects on in vivo seizure sensitivity.




Objects Annotated

Genes (Rattus norvegicus)
Tnf  (tumor necrosis factor)
Tnfrsf1a  (TNF receptor superfamily member 1A)
Tnfrsf1b  (TNF receptor superfamily member 1B)

Genes (Mus musculus)
Tnf  (tumor necrosis factor)
Tnfrsf1a  (tumor necrosis factor receptor superfamily, member 1a)
Tnfrsf1b  (tumor necrosis factor receptor superfamily, member 1b)

Genes (Homo sapiens)
TNF  (tumor necrosis factor)
TNFRSF1A  (TNF receptor superfamily member 1A)
TNFRSF1B  (TNF receptor superfamily member 1B)


Additional Information