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Open Access Highly Accessed Research article

Levetiracetam attenuates hippocampal expression of synaptic plasticity-related immediate early and late response genes in amygdala-kindled rats

Kenneth V Christensen12*, Henrik Leffers2, William P Watson34, Connie Sánchez35, Pekka Kallunki1 and Jan Egebjerg1

Author Affiliations

1 Dept. of Molecular Biology, Discovery Biology Research, H. Lundbeck A/S, DK-2500 Valby, Denmark

2 University Dept. of Growth and Reproduction, Rigshospitalet, DK-2100 Copenhagen, Denmark

3 Dept. of Neuropharmacology, H. Lundbeck A/S, DK-2500 Valby, Denmark

4 Current address: Teva Pharmaceutical Ltd, The Gate House, Gatehouse Way, Aylesbury, UK

5 Current address: Dept. of Neuroscience, Lundbeck Research Inc. USA, Paramus-NJ, USA

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BMC Neuroscience 2010, 11:9  doi:10.1186/1471-2202-11-9

Published: 27 January 2010

Abstract

Background

The 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.

Results

Cyclooxygenase-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.

Conclusions

The 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.