Abstracts

Early-Life Seizures Prime Microglia and Elicit Over-Activation Following Subsequent Seizures Later in Life

Abstract number : 4.044
Submission category : Translational Research-Animal Models
Year : 2006
Submission ID : 6953
Source : www.aesnet.org
Presentation date : 12/1/2006 12:00:00 AM
Published date : Nov 30, 2006, 06:00 AM

Authors :
Patrick D. Fox, Hyokwon Chung, and Sookyong Koh

Chronic epilepsy often starts with an isolated early life seizure, a period of remission, and then the re-emergence of seizures later in life. To mimic this event in rats, we developed a [ldquo]two-hit[rdquo]-kainic acid (KA) model and demonstrated that an early life seizure increases susceptibility to seizures and to seizure-induced neuronal injury in adulthood. We have found that activation of resident microglia and subsequent increases in mRNA of inflammatory cytokines and complements appear to be the key initiating events for seizure-induced inflammatory responses. We hypothesize that the inflammatory reaction provoked by early-life seizures primes the developing brain and microglia, leading to rapid reactivation by a second seizure in adulthood. Blocking of this microglia activation through pharmaceuticals such as minocycline may prevent some neuronal injury typically seen following these later life seizures., Postnatal day 21-25 LE rats were injected with KA (10mg/kg, I.p.) or saline. The first dose of minocycline (10 mg/kg, [italic]i.p.[/italic]) or vehicle was administered immediately after KA injection, and 6 more doses were given 24 hours apart over the next 7 days. Two weeks after KA/PBS injections, all remaining rats were given KA. Rats were perfused two days later and all brain sections were processed for immunocytochemistry (ICC) using IbA1/Aif antibody to visualize activated microglia. CA1 subregions of the hippocampal sections were analyzed using MetaMorph (Universal Imaging Corp.). An average percent of area above the set threshold (threshold area containing immunoreactive cells captured at 20x) and the number of stained cells were calculated per animal., Cellular hypertrophy of microglia suggestive of activated state was observed within 24 h after KA-induced seizures. The group that experienced early-life seizures (K/K) had a marked increase in the number of activated microglia compared to control littermates who received single KA in adulthood (S/K). These microglia were larger and formed a complex, web-like network localized within the hippocampus especially over the CA1 region. Over two fold increase in immunoreactive areas was noted in K/K compared to S/K (KA: 9.0 [plusmn] 1.3 vs. Saline: 4.0 [plusmn] .1.0, p[lt]0.04, [italic]n[/italic]=8). The microglia count was also significantly greater (KA: 233.1 [plusmn] 12.1 vs. Saline 153.5 [plusmn] 9.2, p[lt].039, [italic]n[/italic]=8). This hypertrophic, hyperplastic, reactivating effect of an early-life seizure on microglia was abolished in minocycline treated rats., Our results indicate that the experience of early life seizures primes the microglia and elicits a much more robust activation in response to later life seizures. Whether microglial reactivation is causally related to the epileptogenic effect of early-life seizures to increase seizure susceptibility and cell death will be determined., (Supported by Child Neurology Foundation and K02NS048237.)
Translational Research