Abstracts

Behavioral problems, school failure and memory impairment are common among children with epilepsy. No effective treatment exists to promote recovery and neuron regeneration after seizures; currently used antiepileptic drugs only prevent further seizures. Growing evidence suggests that a stimulating environment and rehabilitation enhance recovery from neuronal injury. We investigated the efficacy of environmental enrichment in reversing seizure-induced changes in behavior and gene expression in developing rats. Postnatal day 20-25 LE male rats were injected with kainic acid (KA,10mg/kg, i.p.) or saline and placed in either singly in a cage, or as a group of 8 in an enriched environment (control-isolated, KA-isolated, control-enriched, and KA-enriched). After7-10 days, exploratory behavior in a novel environment was quantified in the open field test by counting number of squares crossed by an animal during 5 minutes and seizure susceptibility was measured by latency to KA-induced seizures. Microarray-based gene analysis was performed on total RNA isolated from hippocampi dissected from 4 animals per chip. Three independent hybridizations were performed on Affymetrix Genechip[reg] per condition (total of 12 RAE230A profiles) and analyzed using Affymetrix GDAS, Genespring[reg] and SAM softwares. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on select genes to confirm microarray data. Exploratory behavior in KA-isolated rats were decreased in open field while KA rats housed in enriched environment behaved similarly to controls ([italic]n[/italic]=37, ANOVA, [italic]p[/italic][lt]0.001). Exposure to enriched environment following KA also reversed heightened seizure susceptibility at P30. Correlated with an improvement in behavior, an effector immediate early gene and growth factor, Arc (activity regulated cytoskeletal associated protein) as well as zinc finger transcription factors, Erg(early growth response)1 and Erg4, that were decreased by KA seizures, were enhanced in KA-enriched rats. Conversely, increases in inflammation related genes (Cebpd (CCAAT/enhancer binding protein, delta), C1, C3 (complement component 1 [amp] 3), CD74 (MHC class II antigen), Aif1 (allograft inflammatory factor 1) following seizures were reversed by rearing in the enriched environment. Quantitative RT-PCR confirmed these gene expression changes. Our results show the therapeutic efficacy of environmental enrichment in reversing a decrease in exploratory behavior and an increase in seizure susceptibility after early-life seizures. These behavioral changes are accompanied by parallel changes in pro-inflammatory genes and in specific genes involved in learning, memory consolidation and cell proliferation. Our results provide an experimental basis for promoting enriching education programs for children with epilepsy. (Supported by KO8NS02068 and CURE)