Abstract
BackgroundThe amygdala-kindled rat is a model for human temporal lobe epilepsy and activity-dependent synaptic plasticity. Hippocampal RNA isolated from amygdala-kindled rats at different kindling stages was analyzed to identify kindling-induced genes. Furthermore, effects of the anti-epileptic drug levetiracetam on kindling-induced gene expression were examined.ResultsCyclooxygenase-2 (Cox-2), Protocadherin-8 (Pcdh8) and TGF-beta-inducible early response gene-1 (TIEG1) were identified and verified as differentially expressed transcripts in the hippocampus of kindled rats by in situ hybridization and quantitative RT-PCR. In addition, we identified a panel of 16 additional transcripts which included Arc, Egr3/Pilot, Homer1a, Ania-3, MMP9, Narp, c-fos, NGF, BDNF, NT-3, Synaptopodin, Pim1 kinase, TNF-α, RGS2, Egr2/krox-20 and β-A activin that were differentially expressed in the hippocampus of amygdala-kindled rats. The list consists of many synaptic plasticity-related immediate early genes (IEGs) as well as some late response genes encoding transcription factors, neurotrophic factors and proteins that are known to regulate synaptic remodelling. In the hippocampus, induction of IEG expression was dependent on the afterdischarge (AD) duration. Levetiracetam, 40 mg/kg, suppressed the development of kindling measured as severity of seizures and AD duration. In addition, single animal profiling also showed that levetiracetam attenuated the observed kindling-induced IEG expression; an effect that paralleled the anti-epileptic effect of the drug on AD duration.ConclusionsThe present study provides mRNA expression data that suggest that levetiracetam attenuates expression of genes known to regulate synaptic remodelling. In the kindled rat, levetiracetam does so by shortening the AD duration thereby reducing the seizure-induced changes in mRNA expression in the hippocampus.
Highlights
The amygdala-kindled rat is a model for human temporal lobe epilepsy and activity-dependent synaptic plasticity
The initial pairing of animals secured that each levetiracetam treated rat was paired with a vehicle treated control rat, and that the number of stimulations received by the levetiracetam treated rat was matched to that of its pair-housed vehicle treated control rat
Differential expression of “synaptic plasticity related immediate early gene (IEG)” in amygdala-kindled rats Based on the differential expressed transcripts identified in the DDRT-PCR analysis and expression changes of genes related to those transcripts we examined the literature for genes previously reported as involved in models of neuronal or synaptic activity including maximal electroconvulsive shock, kainate induced seizures, long-term potentiation, long-term depression, chronic epilepsy models including amygdalahippocampal kindling as well as models with spontaneous seizure activity after pilocarpine- and PTZinduced status epilepticus
Summary
The amygdala-kindled rat is a model for human temporal lobe epilepsy and activity-dependent synaptic plasticity. The symptomatic forms of human temporal lobe epilepsy results from various kinds of brain injury, e.g. stroke, ischemia, head trauma, infections, febrile seizures and brain surgery [4]. In these cases the epileptic process generally comprises three phases i) the initial precipitating insult ii) the latent epileptogenic phase and iii) epilepsy, i.e. recurrent complex partial seizures with and d) have a similar pharmacological profile [7]. The amygdala-kindling model initially characterized by Goddard and colleagues [8] comprises many if not all of these features of human TLE [5,8,9,10]
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