The cortical innate immune response increases local neuronal excitability leading to seizures

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dc.contributor.authorRodgers, K.
dc.contributor.authorHutchinson, M.
dc.contributor.authorNorthcutt, A.
dc.contributor.authorMaier, S.
dc.contributor.authorWatkins, L.
dc.contributor.authorBarth, D.
dc.date.issued2009
dc.description.abstractBrain glial cells, five times more prevalent than neurons, have recently received attention for their potential involvement in epileptic seizures. Microglia and astrocytes, associated with inflammatory innate immune responses, are responsible for surveillance of brain damage that frequently results in seizures. Thus, an intriguing suggestion has been put forward that seizures may be facilitated and perhaps triggered by brain immune responses. Indeed, recent evidence strongly implicates innate immune responses in lowering seizure threshold in experimental models of epilepsy, yet, there is no proof that they can play an independent role in initiating seizures in vivo. Here, we show that cortical innate immune responses alone produce profound increases of brain excitability resulting in focal seizures. We found that cortical application of lipopolysaccharide, binding to toll-like receptor 4 (TLR4), triples evoked field potential amplitudes and produces focal epileptiform discharges. These effects are prevented by pre-application of interleukin-1 receptor antagonist. Our results demonstrate how the innate immune response may participate in acute seizures, increasing neuronal excitability through interleukin-1 release in response to TLR4 detection of the danger signals associated with infections of the central nervous system and with brain injury. These results suggest an important role of innate immunity in epileptogenesis and focus on glial inhibition, through pharmacological blockade of TLR4 and the pro-inflammatory mediators released by activated glia, in the study and treatment of seizure disorders in humans.
dc.description.statementofresponsibilityKrista M. Rodgers, Mark R. Hutchinson, Alexis Northcutt, Steven F. Maier, Linda R. Watkins and Daniel S. Barth
dc.identifier.citationBrain, 2009; 132(9):2478-2486
dc.identifier.doi10.1093/brain/awp177
dc.identifier.issn0006-8950
dc.identifier.issn1460-2156
dc.identifier.orcidHutchinson, M. [0000-0003-2154-5950]
dc.identifier.urihttp://hdl.handle.net/2440/56013
dc.language.isoen
dc.publisherOxford University Press
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/465423
dc.rights© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
dc.source.urihttps://doi.org/10.1093/brain/awp177
dc.subjectepilepsy
dc.subjectglial cells
dc.subjectLPS
dc.subjectTLR4
dc.subjectIL1
dc.titleThe cortical innate immune response increases local neuronal excitability leading to seizures
dc.typeJournal article
pubs.publication-statusPublished

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