Brain Advance Access published online on June 30, 2009
Brain, doi:10.1093/brain/awp177
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The cortical innate immune response increases local neuronal excitability leading to seizures
1 Department of Psychology and Neuroscience, University of Colorado, UCB 345 Boulder, CO 80309, USA 2 Discipline of Pharmacology, University of Adelaide, Adelaide, South Australia, Australia
Correspondence to:
Daniel S. Barth, Department of Psychology and Neuroscience, University of Colorado, UCB 345, Boulder, CO 80309, USA E-mail: dbarth{at}psych.colorado.edu
Brain 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.
Key Words: epilepsy; glial cells; LPS; TLR4; IL1
Abbreviations:
AEP, auditory evoked potential; BMI, bicuculline methiodide; GABAA, gamma-aminobutyric acid ionotrophic receptor; IL-1, interleukin-1; IL-1ra, interleukin-1 receptor antagonist; LPS, lipopolysaccharide; LPS-RS, LPS derived from the photosynthetic bacterium Rhodobacter sphaeroides; PTZ, pentylenetetrazol; RMS, root mean squared; SEP, somatosensory evoked potential; TBI, traumatic brain injury; TLR4, toll-like receptor 4; TNF
, tumour necrosis factor-; X–A, xylazine–acepromazine; K-X-A, ketamine-xylazine-acepromazine
Received February 6, 2009. Revised April 21, 2009. Accepted May 24, 2009.