Abstracts

Accumulating evidence suggests a funtional role for neuroinflammation as a cause of neuronal excitability and degeneration. Microarray analysis in our laboratory showed a rapid and transient increase of genes coding for classical inflammatory mediators, complements and cytokines after kainic acid (KA) seizures induced at postnatal day (P)15 . We have previously shown that early life seizures, in the absence of cellular infiltration or cell loss, confer susceptibility to future seizures and cause increased neuronal injury when rats have a second seizure in adulthood. To determine whether seizure-induced inflammation plays a direct role in increasing seizure susceptibility after the experience of early-life seizures, we treated rats with minocycline, an inhibitor of microglia activation, or exposed them to enriched environment, which prevents the seizure-induced upregulation of inflammation-related genes. P21 LE male rats were injected with KA (10mg/kg, [italic]i.p.[/italic]) or saline. The first dose of minocycline(10 mg/kg, [italic]i.p.[/italic]) or vehicle (PBS) was administered immediately after KA injection, and 6 more doses were given 24 hours apart over the next 7 days. Separate group of rats were housed either singly in a cage, or as a group of 8 in an enriched environment consisted of a large cage with sensory-motor stimulations.
After14 days (on P35), seizure susceptibility was measured by latency to KA-induced seizures. Rats were perfused two days after KA and brain sections were processed for immunocytochemistry using Aif antibody to visualize activated microglia. Seizure susceptibility to KA on P35 was increased in rats exposed to KA on P21 compared to saline treated littermate (Tukey test, p[lt]0.05). This epileptogenic effect of early-life seizure was reversed by daily minocycline injection for one week after second KA (One way ANOVA, [italic]p[/italic]=0.034, [italic]n[/italic]=27). Minocycline alone did not change latency to KA on P35 nor seizure severity significantly different among treatment groups. Exposing the rats to environmental enrichment after KA for 7-14 days effectively reduced heightened susceptibility to second KA (One way ANOVA, [italic]p[/italic][lt]0.007, [italic]n[/italic]=72). Aif1 immunocytochemistry 48 h after KA on P35 showed hyperplastic and hypertrophic microglia in animals with KA at P21. This effect of early-life seizures was abolished in minocycline treated rats. Our results support the hypothesis that inflammatory or immune reaction provoked by early life seizures sensitizes the developing brain so that microglia are modified or primed leading to rapid reactivation by a second seizure induced in adulthood. (Supported by Davee Foundation and CURE.)