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Characterization of the zinc-sensitive metal-regulatory transcription factor 1 in hippocampal epileptic network formation using an animal model of Temporal Lobe Epilepsy

dc.contributor.advisorBecker, Albert
dc.contributor.authorMeconi, Annachiara
dc.date.accessioned2023-10-02T09:41:16Z
dc.date.issued02.10.2023
dc.identifier.urihttps://hdl.handle.net/20.500.11811/11080
dc.description.abstractTemporal lobe epilepsy (TLE) is the most common form of focal epilepsy. It usually occurs after a transient brain insult, including status epilepticus (SE), which triggers a latent period of epileptogenesis prior to the occurrence of spontaneous seizures. In an experimental animal model, the Metal-regulatory Transcription Factor 1 (Mtf1) mediates the Zn2+-induced upregulation of the T-type Ca2+ channel Cav3.2, leading to an increase in intrinsic excitability of hippocampal neurons. However, Mtf1 emerged relatively recently as a pathogenetically relevant factor involved in the development of TLE and still little is known about its involvement in the process of epileptogenesis. Therefore, in this study we aim to achieve novel insights about Mtf1 with regard to its spatio-temporal location and activation during epileptogenesis, and to identify new Mtf1-downstream targets. Here, we provide evidence that Mtf1 is activated immediately after SE, and that it regulates several genes associated with synaptic plasticity processes. A transcriptional unit was successfully developed which allowed the identification of Mtf1-expressing neurons in vivo and the monitoring of Mtf1 activation during epileptogenesis. Adeno-associated virus (rAAV) transfer of Mtf1 and a dominant-negative form of Mtf1 (dnMtf1) in hippocampal neurons resulted in an increase of cAMP responsive element binding protein 1 (Creb1) mRNA expression. The kinetics of Creb1 expression followed the expression levels of Mtf1 in the hippocampal subregions of pilocarpine-SE animals. Immunofluorescence of murine slices showed a stronger Creb1 protein expression in neurons containing nuclear-activated Mtf1. Data from resected hippocampi of pharmacoresistant patients affected by TLE associated with hippocampal sclerosis support the Zn2+-Mtf1-Creb1 pathway. Finally, RNA-sequencing from dissected murine hippocampi transduced with Mtf1 and dnMtf1 revealed the Immunoglobulin Heavy Constant Gamma 1 (Ighg1), Serotonin 5-HT-2A Receptor (Htr2a) and the Dopamine Receptor D2 (Drd2) as downstream target genes of Mtf1. This work uncovered a novel transcription factor regulated transcript module in the process of epileptogenesis and provides new prospects for preventing and treating TLE.de
dc.language.isoeng
dc.rightsIn Copyright
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectTemporal Lobe Epilepsy
dc.subjectepileptogenesis
dc.subjectTranscription Factor
dc.subjectMtf1
dc.subjectCreb1
dc.subjectTranscriptional unit
dc.subjectPilocarpine-animal model
dc.subjectCav3.2
dc.subjectZinc
dc.subject.ddc570 Biowissenschaften, Biologie
dc.subject.ddc610 Medizin, Gesundheit
dc.titleCharacterization of the zinc-sensitive metal-regulatory transcription factor 1 in hippocampal epileptic network formation using an animal model of Temporal Lobe Epilepsy
dc.typeDissertation oder Habilitation
dc.publisher.nameUniversitäts- und Landesbibliothek Bonn
dc.publisher.locationBonn
dc.rights.accessRightsembargoedAccess
dc.date.embargoEndDate01.10.2025
dc.identifier.urnhttps://nbn-resolving.org/urn:nbn:de:hbz:5-72620
ulbbn.pubtypeErstveröffentlichung
ulbbnediss.affiliation.nameRheinische Friedrich-Wilhelms-Universität Bonn
ulbbnediss.affiliation.locationBonn
ulbbnediss.thesis.levelDissertation
ulbbnediss.dissID7262
ulbbnediss.date.accepted25.09.2023
ulbbnediss.instituteMedizinische Fakultät / Institute : Institut für Neuropathologie
ulbbnediss.fakultaetMedizinische Fakultät
dc.contributor.coRefereeLory, Philippe
ulbbnediss.contributor.orcidhttps://orcid.org/0000-0003-3592-8098


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