Abstracts

Depression is the most common psychiatric comorbidity of epilepsy, affecting over 30% of people with epilepsy. Whether this elevated risk of depression is due to the biology of epilepsy specifically or is attributable to the psychosocial burden of chronic neurological condition remains unknown. To better understand the contribution of seizures versus environment as causes of depression in epilepsy, we investigated differential gene expression and behavioral changes in juvenile rats reared in different environments after kainic acid (KA) induced seizures. LE male rats were injected with KA (10mg/kg, i.p.) or saline on postnatal day 20-25 and were housed either singly in a cage or as a group of 8 in an enriched environment that allowed social and sensory motor stimulation (control-isolated, KA-isolated, control-enriched and KA-enriched). 7-14 days after injection, animals underwent exploratory behavior and Porsolt swim tests. Exploratory behavior was quantified by counting the total number of squares crossed by an animal over 5 minutes. The Porsolt swim test, measure of behavioral despair, quantified the amount of time spent swimming versus immobile when animals were placed for 300 seconds in a water filled cylinder. Microarray-based gene analysis was performed on total RNA isolated from 12 hippocampi and pooled for triplicate Affymetrix genechips. Real time quantitative RT-PCR was performed to confirm microarray data. Exploratory behavior was significantly impaired in KA animals reared in isolation Control-isolated rats were also affected, but to a lesser degree (one-way ANOVA, [italic]p[/italic][lt]0.0001, [italic]n[/italic]=112). Similar trends were noted for mobility in Porsolt swim test. (one-way ANOVA, [italic]p[/italic]=0.0508, [italic]n[/italic]=15). KA-isolated rats exhibited 31% mobility (92/300 sec) while KA and control-enriched rats were mobile 52% and 56% of total time, respectively. We selected for genes that are both significantly downregulated by KA seizures and upregulated by environmental enrichment. This common gene selection process yielded two known genes involved in mood, affect and sleep regulation: serotonin receptor 5B (5-HTr5b) and histamine receptor (H3r). qRT-PCR confirmed the results. Early-life seizures caused a decrease in exploratory behavior, immobility in the Porsolt swim test and a decrease in serotonin and histamine receptor gene expression. Isolation appears to exacerbate these seizure-induced changes in behavior and gene expression, while environmental enrichment mitigated these effects. Our results suggest that, while seizures themselves may lead to increased susceptibility to depression through transcriptional regulation, environmental interaction may counteract the disease process and influence the behavioral outcome of epilepsy. (Supported by Davee Foundation and CURE.)