title: Developmental changes in Notch1 and NLE1 expression in a genetic model of absence epilepsy.
abstract: Childhood absence epilepsy (CAE) is an epilepsy syndrome with seizures occurring in the early childhood, highlighting that seizures susceptibility in CAE is dependent on brain development. The Notch 1 signalling pathway is important in brain development, yet the role of the Notch1 signalling pathway in CAE remains elusive. We here explored Notch1 and its modulator notchless homologue 1 (NLE1) expression in WAG/Rij and control rats using immunohistochemistry. Functional Notch 1 effects were assessed in WAG/Rij rats in vivo. WAG/Rij rats lack the developmental increase in cortical Notch1 and NLE 1 mRNA expression seen in controls, and Notch 1 and NLE1 mRNA and protein expression were lower in somatosensory cortices of WAG/Rij rats when compared to controls. This coincided with an overall decreased cortical GFAP expression in the early development in WAG/Rij rats. These effects were region-specific as they were not observed in thalamic tissues. Neuron-to-glia ratio as a marker of the impact of Notch signalling on differentiation was higher in layer 4 of somatosensory cortex of WAG/Rij rats. Acute application of Notch 1 agonist Jagged 1 suppressed, whereas DAPT, a Notch antagonist, facilitated spike and wave discharges (SWDs) in WAG/Rij rats. These findings point to Notch1 as an important signalling pathway in CAE which likely shapes architectural organization of the somatosensory cortex, a region critically involved in developmental epileptogenesis in CAE. More immediate effects of Notch 1 signalling are seen on in vivo SWDs in CAE, pointing to the Notch 1 pathway as a possible treatment target in CAE.
authors.affiliation: Shefa Neuroscience Research Centre, Khatam Alanbia Hospital, Tehran, Iran.|Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Fariba
authors.initials: F
authors.lastname: Karimzadeh
authors.affiliation: Shefa Neuroscience Research Centre, Khatam Alanbia Hospital, Tehran, Iran.
authors.forename: Sayed Mostafa
authors.initials: SM
authors.lastname: Modarres Mousavi
authors.affiliation: Shefa Neuroscience Research Centre, Khatam Alanbia Hospital, Tehran, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Alipour
authors.affiliation: Shefa Neuroscience Research Centre, Khatam Alanbia Hospital, Tehran, Iran.
authors.forename: Hassan
authors.initials: H
authors.lastname: Hosseini Ravandi
authors.affiliation: Department of Neurology, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Stjepana
authors.initials: S
authors.lastname: Kovac
authors.affiliation: Shefa Neuroscience Research Centre, Khatam Alanbia Hospital, Tehran, Iran. gorjial@uni-muenster.de.|Department of Neurology, Westfälische Wilhelms-Universität Münster, Münster, Germany. gorjial@uni-muenster.de.|Epilepsy Research Center, Department of Neurosurgery, Westfälische Wilhelms-Universität Münster, Robert-Koch-Straße 45, 48149, Münster, Germany. gorjial@uni-muenster.de.|Department of Neuroscience, Mashhad University of Medical Sciences, Mashhad, Iran. gorjial@uni-muenster.de.
authors.forename: Ali
authors.initials: A
authors.lastname: Gorji
mesh_terms: D000367:Age Factors; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D058256:Brain Waves; D004195:Disease Models, Animal; D000069280:Electrocorticography; D004832:Epilepsy, Absence / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D000072100:Jagged-1 Protein / Q000008:administration & dosage; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010641:Phenotype; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013003:Somatosensory Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D013788:Thalamus / Q000378:metabolism / Q000503:physiopathology
chemical_list: D034961:Antigens, Nuclear; C000614142:Gfap protein, rat; D005904:Glial Fibrillary Acidic Protein; D000072100:Jagged-1 Protein; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C497763:Notch1 protein, rat; C546339:Rbfox3 protein, rat; D051881:Receptor, Notch1
keywords: Absence epilepsy; Brain development; Electroencephalogram; Neurobiology