Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy

Heinrich, Christophe; Lähteinen, Sari; Suzuki, Fumio; Laharie, Anne-Marie; Huber, Susanne; Häussler, Ute; Haas, Carola A.; Larmet, Yves; Ċastrén, Eero; Depaulis, Antoine

doi:10.1016/j.nbd.2011.01.001

Cited by 169 publications

(193 citation statements)

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“…In the present study, we provide an overview of the temporal proteomic regulation that takes place during development of epilepsy, in a well-defined model of MTLE 16,25 . For this reason, distinct time-points after KA injection were selected for further analysis.…”

Section: Discussionmentioning

confidence: 99%

“…induced an initially focal status epilepticus lasting up to 15-20h, during which animals showed mild asymmetric clonic movements of the forelimbs, rotations, and/or behavioral arrests [13][14][15][16][17][18] . Following KA administration, all mice evaluated in this study had behavioral signs of SE on day 0.…”

Section: Intrahippocampal Kainate Injection Induces Initial Status Epmentioning

confidence: 99%

“…Following KA administration, all mice evaluated in this study had behavioral signs of SE on day 0. Then, they progressively displayed 15-20 sec duration focal seizures associated with behavioral arrest, chewing and head nodding during the first 2-3 weeks 14,16 . As described earlier (methods), mice were not implanted with electrodes in these experiments.…”

Section: Intrahippocampal Kainate Injection Induces Initial Status Epmentioning

confidence: 99%

“…Indeed, in this model, spontaneous focal epileptic seizures associated with mild behavioral expression develop progressively in the hippocampus, leading to a stereotyped pattern at 16-18 days following KA injection, which remains stable for several months, with only occasional propagation to the cortex, as in MTLE patients 16,17 . In addition, cell loss in CA1, CA3 and hilus areas, as well as astrocyte proliferation and granule cell dispersion are observed in the kainateinjected hippocampus, that are highly reminiscent of the hippocampal sclerosis 4 observed in most MTLE patients 13,14,18 .…”

Section: Introductionmentioning

confidence: 97%

“…Here, we used a mouse model of MTLE induced by intra-hippocampal injection of kainate (KA) which reproduces most of the histopathological and electrophysiological features of human MTLE [13][14][15][16] . Indeed, in this model, spontaneous focal epileptic seizures associated with mild behavioral expression develop progressively in the hippocampus, leading to a stereotyped pattern at 16-18 days following KA injection, which remains stable for several months, with only occasional propagation to the cortex, as in MTLE patients 16,17 .…”

Section: Introductionmentioning

confidence: 99%

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High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

Bitsika

Duveau²,

Simon-Areces

et al. 2016

J. Proteome Res.

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Uncovering the molecular mechanisms of Mesial temporal lobe epilepsy (MTLE) is critical to identify therapeutic targets. In this study, we performed global protein expression analysis of a kainic acid (KA) MTLE mouse model at various time-points (1d, 3d, 30d post KA injection -dpi), representing specific stages of the syndrome.High resolution liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), in combination to label-free protein quantification, using three processing approaches for quantification, was applied. Following comparison of KA versus NaCl-injected mice, 22, 53 and 175 proteins were differentially (statistically significant) expressed at 1, 3 and 30dpi respectively, according to all 3 quantification approaches. Selected findings were confirmed by multiple reaction monitoring LC-MS/MS. As a positive control, the astrocyte marker GFAP was found to be upregulated (3dpi:1.9 fold; 30dpi:12.5 fold), also verified by IHC. The results collectively suggest that impairment in synaptic transmission occurs even right after initial status epilepticus (1dpi), with neurodegeneration becoming more extensive during epileptogenesis (3dpi) and sustained at the chronic phase (30dpi), where also extensive glial and astrocyte-mediated inflammation is evident. This molecular profile is in line with observed phenotypic changes in human MTLE, providing the basis for future studies on new molecular targets for the disease.

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Section: Discussionmentioning

confidence: 99%

Section: Intrahippocampal Kainate Injection Induces Initial Status Epmentioning

confidence: 99%

Section: Intrahippocampal Kainate Injection Induces Initial Status Epmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

Bitsika

Duveau²,

Simon-Areces

et al. 2016

J. Proteome Res.

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Epilepsy: Animal Models to Reproduce Human Etiopathology

Guillemain

Heinrich

Depaulis

2014

In Vivo Models for Drug Discovery

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Methionine increases BDNF DNA methylation and improves memory in epilepsy

Parrish

Buckingham

Mascia

et al. 2015

Ann Clin Transl Neurol

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ObjectiveTemporal lobe epilepsy (TLE) patients exhibit signs of memory impairments even when seizures are pharmacologically controlled. Surprisingly, the underlying molecular mechanisms involved in TLE-associated memory impairments remain elusive. Memory consolidation requires epigenetic transcriptional regulation of genes in the hippocampus; therefore, we aimed to determine how epigenetic DNA methylation mechanisms affect learning-induced transcription of memory-permissive genes in the epileptic hippocampus.MethodsUsing the kainate rodent model of TLE and focusing on the brain-derived neurotrophic factor (Bdnf) gene as a candidate of DNA methylation-mediated transcription, we analyzed DNA methylation levels in epileptic rats following learning. After detection of aberrant DNA methylation at the Bdnf gene, we investigated functional effects of altered DNA methylation on hippocampus-dependent memory formation in our TLE rodent model.ResultsWe found that behaviorally driven BdnfDNA methylation was associated with hippocampus-dependent memory deficits. Bisulfite sequencing revealed that decreased BdnfDNA methylation levels strongly correlated with abnormally high levels of BdnfmRNA in the epileptic hippocampus during memory consolidation. Methyl supplementation via methionine (Met) increased BdnfDNA methylation and reduced BdnfmRNA levels in the epileptic hippocampus during memory consolidation. Met administration reduced interictal spike activity, increased theta rhythm power, and reversed memory deficits in epileptic animals. The rescue effect of Met treatment on learning-induced BdnfDNA methylation, Bdnf gene expression, and hippocampus-dependent memory, were attenuated by DNA methyltransferase blockade.InterpretationOur findings suggest that manipulation of DNA methylation in the epileptic hippocampus should be considered as a viable treatment option to ameliorate memory impairments associated with TLE.

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Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy

Cited by 169 publications

References 59 publications

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

Epilepsy: Animal Models to Reproduce Human Etiopathology

Methionine increases BDNF DNA methylation and improves memory in epilepsy

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