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The Journal of Neuroscience, July 2, 2008, 28(27):6904-6913; doi:10.1523/JNEUROSCI.1901-08.2008

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Neurobiology of Disease
Postnatal Inflammation Increases Seizure Susceptibility in Adult Rats

Michael A. Galic,¹ Kiarash Riazi,² James G. Heida,¹ Abdeslam Mouihate,² Neil M. Fournier,⁴ Sarah J. Spencer,² Lisa E. Kalynchuk,⁴ G. Campbell Teskey,³ and Quentin J. Pittman²

Epilepsy and Brain Circuits Program, Hotchkiss Brain Institute, Departments of ¹Neuroscience, ²Physiology and Biophysics, and ³Psychology, University of Calgary, Calgary, Alberta, Canada T2N 4N1, and ⁴Neural Systems and Plasticity Research Group, Department of Psychology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5A5

Correspondence should be addressed to Michael A. Galic, Hotchkiss Brain Institute, Epilepsy and Brain Circuits Program, Department of Neuroscience, Faculty of Medicine, University of Calgary, Health Sciences Centre, 3330 Hospital Drive Northwest, Calgary, Alberta, Canada T2N 4N1. Email: magalic{at}ucalgary.ca

There are critical postnatal periods during which even subtle interventions can have long-lasting effects on adult physiology. We asked whether an immune challenge during early postnatal development can alter neuronal excitability and seizure susceptibility in adults. Postnatal day 14 (P14) male Sprague Dawley rats were injected with the bacterial endotoxin lipopolysaccharide (LPS), and control animals received sterile saline. Three weeks later, extracellular recordings from hippocampal slices revealed enhanced field EPSP slopes after Schaffer collateral stimulation and increased epileptiform burst-firing activity in CA1 after 4-aminopyridine application. Six to 8 weeks after postnatal LPS injection, seizure susceptibility was assessed in response to lithium–pilocarpine, kainic acid, and pentylenetetrazol. Rats treated with LPS showed significantly greater adult seizure susceptibility to all convulsants, as well as increased cytokine release and enhanced neuronal degeneration within the hippocampus after limbic seizures. These persistent increases in seizure susceptibility occurred only when LPS was given during a critical postnatal period (P7 and P14) and not before (P1) or after (P20). This early effect of LPS on adult seizures was blocked by concurrent intracerebroventricular administration of a tumor necrosis factor (TNF) antibody and mimicked by intracerebroventricular injection of rat recombinant TNF. Postnatal LPS injection did not result in permanent changes in microglial (Iba1) activity or hippocampal cytokine [IL-1β (interleukin-1β) and TNF] levels, but caused a slight increase in astrocyte (GFAP) numbers. These novel results indicate that a single LPS injection during a critical postnatal period causes a long-lasting increase in seizure susceptibility that is strongly dependent on TNF.

Key words: development; lipopolysaccharide; seizure; cytokine; tumor necrosis factor ; interleukin-1β

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Received Nov. 22, 2007; accepted May 19, 2008.

Correspondence should be addressed to Michael A. Galic, Hotchkiss Brain Institute, Epilepsy and Brain Circuits Program, Department of Neuroscience, Faculty of Medicine, University of Calgary, Health Sciences Centre, 3330 Hospital Drive Northwest, Calgary, Alberta, Canada T2N 4N1. Email: magalic{at}ucalgary.ca

This article has been cited by other articles:

				M. A. Galic, S. J. Spencer, A. Mouihate, and Q. J. Pittman Postnatal programming of the innate immune response Integr. Comp. Biol., September 1, 2009; 49(3): 237 - 245. [Abstract] [Full Text] [PDF]

				N. M. Amankulor, D. Hambardzumyan, S. M. Pyonteck, O. J. Becher, J. A. Joyce, and E. C. Holland Sonic Hedgehog Pathway Activation Is Induced by Acute Brain Injury and Regulated by Injury-Related Inflammation J. Neurosci., August 19, 2009; 29(33): 10299 - 10308. [Abstract] [Full Text] [PDF]

				C. Savin, J. Triesch, and M. Meyer-Hermann Epileptogenesis due to glia-mediated synaptic scaling J R Soc Interface, August 6, 2009; 6(37): 655 - 668. [Abstract] [Full Text] [PDF]

				S. Balosso, M. Maroso, M. Sanchez-Alavez, T. Ravizza, A. Frasca, T. Bartfai, and A. Vezzani A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1{beta} Brain, December 1, 2008; 131(12): 3256 - 3265. [Abstract] [Full Text] [PDF]

				K. Riazi, M. A. Galic, J. B. Kuzmiski, W. Ho, K. A. Sharkey, and Q. J. Pittman Microglial activation and TNF{alpha} production mediate altered CNS excitability following peripheral inflammation PNAS, November 4, 2008; 105(44): 17151 - 17156. [Abstract] [Full Text] [PDF]

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