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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 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 weeksafterpostnatalLPSinjection,seizuresusceptibilitywasassessedinresponsetolithiumCpilocarpine,kainicacid,andpentylenetet- razol. 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 suscep- tibility 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 perma- nentchangesinmicroglial(Iba1)activityorhippocampalcytokine[IL-1?(interleukin-1?)andTNF?]levels,butcausedaslightincrease 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-1? Introduction Seizures in adults can be caused by any number of genetic factors or acquired clinical pathologies. However, in the face of such factors, there is substantial variation in both the likelihood that an individual will develop a seizure and in the severity of the condition. The relative contributions of genetic, environmental, and traumatic conditions to this diversity remain unknown. It has been postulated that early life events, for example a postnatal seizure brought about by whole-body hyperthermia, may predis- pose the brain to epilepsy later in life (Dube ? et al., 2006). Mounting evidence indicates that brief systemic inflamma- tion during critical periods of development, although not associ- ated with obvious CNS injury, may result in long-lasting cerebral and peripheral vulnerability (programming or sensitization) well into adulthood (Eklind et al., 2005;

Hagberg and Mallard, 2005;

Godbout and Johnson, 2006). For example, adult rats that had been treated at postnatal day

14 (P14) with the immune activator lipopolysaccharide (LPS) showed increased brain NMDA recep- tor mRNA (Harre ? et al., 2008) and greater neuronal loss after global cerebral ischemia (Spencer et al., 2006a). Moreover, a sim- ilar postnatal treatment was also sufficient to evoke differences in pain sensitivity (Boisse ? et al., 2005), memory performance (Bilbo et al., 2005), and neuroimmune responses (Boisse ? et al., 2004) in adulthood. Consequently, it appears that the immature brain can be permanently modified after a single inflammatory episode in a manner that may contribute to a number of behavioral and phys- iological abnormalities. The inflammatory response brought about by LPS is charac- terized by the generation of cytokines in the periphery and con- comitant synthesis in the CNS (Laye ? et al., 1994;