Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy
Mesio-temporal lobe epilepsy (MTLE), the most common drug-resistant epilepsy syndrome, is characterized by the recurrence of spontaneous focal seizures after a latent period that follows, in most patients, an initial insult during early childhood. Many of the mechanisms that have been associated wit...
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doaj-7c3b6ca7791642d0a4c7e5d769fe08f82021-03-22T12:36:21ZengElsevierNeurobiology of Disease1095-953X2011-04-014213547Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsyChristophe Heinrich0Sari Lähteinen1Fumio Suzuki2Laharie Anne-Marie3Susanne Huber4Ute Häussler5Carola Haas6Yves Larmet7Eero Castren8Antoine Depaulis9Grenoble Institut des Neurosciences, INSERM U836-UJF-CEA-CHU, Dynamique des Réseaux Synchrones Epileptiques, Université Joseph Fourier, Grenoble, FranceLaboratory of Molecular Pharmacology, A.I. Virtanen Institute, Kuopio, FinlandDepartments of Neurosurgery and Anatomy, Shiga University of Medical Science, Ohtsu, JapanGrenoble Institut des Neurosciences, INSERM U836-UJF-CEA-CHU, Dynamique des Réseaux Synchrones Epileptiques, Université Joseph Fourier, Grenoble, FranceExperimental Epilepsy Group, Neurocenter, University of Freiburg, Freiburg, GermanyExperimental Epilepsy Group, Neurocenter, University of Freiburg, Freiburg, GermanyExperimental Epilepsy Group, Neurocenter, University of Freiburg, Freiburg, GermanyINSERM U692, Signalisation Moléculaire et Neurodégénérescence, Strasbourg, FranceNeuroscience Center, University of Helsinki, Helsinki, FinlandGrenoble Institut des Neurosciences, INSERM U836-UJF-CEA-CHU, Dynamique des Réseaux Synchrones Epileptiques, Université Joseph Fourier, Grenoble, France; Corresponding author. Center de Recherche INSERM U836-UJF-CEA-CHU, Université Joseph Fourier, Faculté de Médecine, Domaine de la Merci, 38706 La Tronche Cedex, France. Fax: +33 4 56 52 06 57.Mesio-temporal lobe epilepsy (MTLE), the most common drug-resistant epilepsy syndrome, is characterized by the recurrence of spontaneous focal seizures after a latent period that follows, in most patients, an initial insult during early childhood. Many of the mechanisms that have been associated with the pathophysiology of MTLE are known to be regulated by brain-derived neurotrophic factor (BDNF) in the healthy brain and an excess of this neurotrophin could therefore play a critical role in MTLE development. However, such a function remains controversial as other studies revealed that BDNF could, on the contrary, exert protective effects regarding epilepsy development. In the present study, we further addressed the role of increased BDNF/TrkB signaling on the progressive development of hippocampal seizures in the mouse model of MTLE obtained by intrahippocampal injection of kainate. We show that hippocampal seizures progressively developed in the injected hippocampus during the first two weeks following kainate treatment, within the same time-frame as a long-lasting and significant increase of BDNF expression in dentate granule cells. To determine whether such a BDNF increase could influence hippocampal epileptogenesis via its TrkB receptors, we examined the consequences of (i) increased or (ii) decreased TrkB signaling on epileptogenesis, in transgenic mice overexpressing the (i) TrkB full-length or (ii) truncated TrkB-T1 receptors of BDNF. Epileptogenesis was significantly facilitated in mice with increased TrkB signaling but delayed in mutants with reduced TrkB signaling. In contrast, TrkB signaling did not influence granule cell dispersion, an important feature of this mouse model which is also observed in most MTLE patients. These results suggest that an increase in TrkB signaling, mediated by a long-lasting BDNF overexpression in the hippocampus, promotes epileptogenesis in MTLE.http://www.sciencedirect.com/science/article/pii/S0969996111000027NeurotrophinNeuronal plasticityDentate gyrusAmmon's horn sclerosisGranule cell dispersion |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Christophe Heinrich Sari Lähteinen Fumio Suzuki Laharie Anne-Marie Susanne Huber Ute Häussler Carola Haas Yves Larmet Eero Castren Antoine Depaulis |
spellingShingle |
Christophe Heinrich Sari Lähteinen Fumio Suzuki Laharie Anne-Marie Susanne Huber Ute Häussler Carola Haas Yves Larmet Eero Castren Antoine Depaulis Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy Neurobiology of Disease Neurotrophin Neuronal plasticity Dentate gyrus Ammon's horn sclerosis Granule cell dispersion |
author_facet |
Christophe Heinrich Sari Lähteinen Fumio Suzuki Laharie Anne-Marie Susanne Huber Ute Häussler Carola Haas Yves Larmet Eero Castren Antoine Depaulis |
author_sort |
Christophe Heinrich |
title |
Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy |
title_short |
Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy |
title_full |
Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy |
title_fullStr |
Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy |
title_full_unstemmed |
Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy |
title_sort |
increase in bdnf-mediated trkb signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2011-04-01 |
description |
Mesio-temporal lobe epilepsy (MTLE), the most common drug-resistant epilepsy syndrome, is characterized by the recurrence of spontaneous focal seizures after a latent period that follows, in most patients, an initial insult during early childhood. Many of the mechanisms that have been associated with the pathophysiology of MTLE are known to be regulated by brain-derived neurotrophic factor (BDNF) in the healthy brain and an excess of this neurotrophin could therefore play a critical role in MTLE development. However, such a function remains controversial as other studies revealed that BDNF could, on the contrary, exert protective effects regarding epilepsy development. In the present study, we further addressed the role of increased BDNF/TrkB signaling on the progressive development of hippocampal seizures in the mouse model of MTLE obtained by intrahippocampal injection of kainate. We show that hippocampal seizures progressively developed in the injected hippocampus during the first two weeks following kainate treatment, within the same time-frame as a long-lasting and significant increase of BDNF expression in dentate granule cells. To determine whether such a BDNF increase could influence hippocampal epileptogenesis via its TrkB receptors, we examined the consequences of (i) increased or (ii) decreased TrkB signaling on epileptogenesis, in transgenic mice overexpressing the (i) TrkB full-length or (ii) truncated TrkB-T1 receptors of BDNF. Epileptogenesis was significantly facilitated in mice with increased TrkB signaling but delayed in mutants with reduced TrkB signaling. In contrast, TrkB signaling did not influence granule cell dispersion, an important feature of this mouse model which is also observed in most MTLE patients. These results suggest that an increase in TrkB signaling, mediated by a long-lasting BDNF overexpression in the hippocampus, promotes epileptogenesis in MTLE. |
topic |
Neurotrophin Neuronal plasticity Dentate gyrus Ammon's horn sclerosis Granule cell dispersion |
url |
http://www.sciencedirect.com/science/article/pii/S0969996111000027 |
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