Levetiracetam Attenuates Hippocampal Expression of Synaptic Plasticity-related Immediate Early and Late Response Genes in Amygdala-kindled Rats

Overview

Journal BMC Neurosci

Publisher Biomed Central

Specialty Neurology

Date 2010 Jan 29

PMID 20105316

Citations 24

Authors

Kenneth V Christensen

Henrik Leffers

William P Watson

Connie Sanchez

Pekka Kallunki

Jan Egebjerg

Affiliations

Soon will be listed here.

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-alpha, RGS2, Egr2/krox-20 and beta-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.

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References

Heaney D, MacDonald B, Everitt A, Stevenson S, Leonardi G, Wilkinson P . Socioeconomic variation in incidence of epilepsy: prospective community based study in south east England. BMJ. 2002; 325(7371):1013-6. PMC: 131020. DOI: 10.1136/bmj.325.7371.1013. View

Winer J, Jung C, Shackel I, Williams P . Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal Biochem. 1999; 270(1):41-9. DOI: 10.1006/abio.1999.4085. View

Scheffer I, Berkovic S . The genetics of human epilepsy. Trends Pharmacol Sci. 2003; 24(8):428-33. DOI: 10.1016/S0165-6147(03)00194-9. View

Loscher W, Honack D . Profile of ucb L059, a novel anticonvulsant drug, in models of partial and generalized epilepsy in mice and rats. Eur J Pharmacol. 1993; 232(2-3):147-58. DOI: 10.1016/0014-2999(93)90768-d. View

Arion D, Sabatini M, Unger T, Pastor J, Alonso-Nanclares L, Ballesteros-Yanez I . Correlation of transcriptome profile with electrical activity in temporal lobe epilepsy. Neurobiol Dis. 2006; 22(2):374-87. DOI: 10.1016/j.nbd.2005.12.012. View

Hendriksen H, Datson N, Ghijsen W, van Vliet E, da Silva F, Gorter J . Altered hippocampal gene expression prior to the onset of spontaneous seizures in the rat post-status epilepticus model. Eur J Neurosci. 2001; 14(9):1475-84. DOI: 10.1046/j.0953-816x.2001.01778.x. View

Eisch A, Lammers C, Yajima S, Mouradian M, Nestler E . In vivo regulation of glial cell line-derived neurotrophic factor-inducible transcription factor by kainic acid. Neuroscience. 1999; 94(2):629-36. DOI: 10.1016/s0306-4522(99)00302-4. View

Roth S, Sommer C, Mundel P, Kiessling M . Expression of synaptopodin, an actin-associated protein, in the rat hippocampus after limbic epilepsy. Brain Pathol. 2001; 11(2):169-81. PMC: 8098178. DOI: 10.1111/j.1750-3639.2001.tb00389.x. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

10.

Isackson P, Huntsman M, Murray K, Gall C . BDNF mRNA expression is increased in adult rat forebrain after limbic seizures: temporal patterns of induction distinct from NGF. Neuron. 1991; 6(6):937-48. DOI: 10.1016/0896-6273(91)90234-q. View

11.

Herman S . Epilepsy after brain insult: targeting epileptogenesis. Neurology. 2002; 59(9 Suppl 5):S21-6. DOI: 10.1212/wnl.59.9_suppl_5.s21. View

12.

Yamazaki M, Matsuo R, Fukazawa Y, Ozawa F, Inokuchi K . Regulated expression of an actin-associated protein, synaptopodin, during long-term potentiation. J Neurochem. 2001; 79(1):192-9. DOI: 10.1046/j.1471-4159.2001.00552.x. View

13.

Morgan J, Cohen D, Hempstead J, Curran T . Mapping patterns of c-fos expression in the central nervous system after seizure. Science. 1987; 237(4811):192-7. DOI: 10.1126/science.3037702. View

14.

Hosford D, Simonato M, Cao Z, Garcia-Cairasco N, Silver J, Butler L . Differences in the anatomic distribution of immediate-early gene expression in amygdala and angular bundle kindling development. J Neurosci. 1995; 15(3 Pt 2):2513-23. PMC: 6578174. View

15.

Yasuda S, Tanaka H, Sugiura H, Okamura K, Sakaguchi T, Tran U . Activity-induced protocadherin arcadlin regulates dendritic spine number by triggering N-cadherin endocytosis via TAO2beta and p38 MAP kinases. Neuron. 2007; 56(3):456-71. PMC: 2424284. DOI: 10.1016/j.neuron.2007.08.020. View

16.

Watanabe Y, Johnson R, Butler L, Binder D, Spiegelman B, Papaioannou V . Null mutation of c-fos impairs structural and functional plasticities in the kindling model of epilepsy. J Neurosci. 1996; 16(12):3827-36. PMC: 6578612. View

17.

Cole A, Saffen D, Baraban J, Worley P . Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation. Nature. 1989; 340(6233):474-6. DOI: 10.1038/340474a0. View

18.

Shin C, McNamara J, Morgan J, Curran T, Cohen D . Induction of c-fos mRNA expression by afterdischarge in the hippocampus of naive and kindled rats. J Neurochem. 1990; 55(3):1050-5. DOI: 10.1111/j.1471-4159.1990.tb04595.x. View

19.

Yamagata K, Andreasson K, Kaufmann W, Barnes C, Worley P . Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron. 1993; 11(2):371-86. DOI: 10.1016/0896-6273(93)90192-t. View

20.

Hefferan T, Subramaniam M, Khosla S, Riggs B, Spelsberg T . Cytokine-specific induction of the TGF-beta inducible early gene (TIEG): regulation by specific members of the TGF-beta family. J Cell Biochem. 2000; 78(3):380-90. DOI: 10.1002/1097-4644(20000901)78:3<380::aid-jcb4>3.0.co;2-l. View