Abstracts

Rationale: Seizures occur when the balance between excitation and inhibition shifts towards excitation. The NMDA-Receptor (NMDAR)is an ionotropic glutamate receptor important in synaptic plasticity (LTP) and pathologic conditions such as epilepsy. Binding of glutamate activates NMDAR, an influx of calcium, and subsequent activation of second messenger systems. The Wnt signaling pathway is a cell signaling pathway misregulated in cancers important in governing synaptic plasticity. The spontaneous CA3 population bursts are an in-vitro model for interictal EEG spikes, proposed to drive epileptogenesis . Epileptiform activity of the hippocampal CA3 region is associated with LTP of hippocampal CA3-CA3 synapses, which may sustain epileptic-like activity. We previously showed that activating Wnt signaling in brain slices increases CA3 network excitability in brain slices (SFN Abstract 2008). Based upon these findings, we hypothesized that Wnt signaling would be upregulated in a whole animal following kainate-induced status epilepticus (KA-SE). We have previously characterized changes in Wnt signaling following KA-SE in adult Sprague Dawley Male Rats (AES Abstract 2010). We now expand our findings to mice.Methods: Adult male C57Bl6 mice were treated with KA 30 mg/kg IP. Behavioral changes following SE were observed. Animals were sacrificed 1 hr, 2 hr, 6 hr, 24 hr, 3 day and 7 days post-KA treatment. Control animals were given an equivalent volume of normal saline. Protein levels (western blot), RNA levels (qRT-PCR) and histological analysis were performed.Results: Cell death, measured by FloroJade, was seen prominently in CA1 and CA3 in animals at 7 days. Immediately following KA-SE, there is a rapid increase in Axin 2 and cMyc (two Wnt target genes) in the hippocampus and frontal cortex beginning as early as 1 hr. and maximal at 3 hr. cMyc remained elevated for 6 to 12 hours.Conclusions: These results suggested that there is an increase in Wnt signaling in KA-treated vs. control animals. KA induction of Wnt signaling was further examined in BAT-Gal mice, in which beta-galactosidase activity is induced in response to Wnt signaling. Further investigation of this cell-signaling pathway may provide novel therapeutic insights for epilepsy