title: Mild overexpression of Mecp2 in mice causes a higher susceptibility toward seizures.
abstract: An intriguing finding about the gene encoding methyl-CpG binding protein 2 (MeCP2) is that the loss-of-function mutations cause Rett syndrome and duplication (gain-of-function) of MECP2 leads to another neurological disorder termed MECP2 duplication syndrome. To ensure proper neurodevelopment, a precise regulation of MeCP2 expression is critical, and any gain or loss of MeCP2 over a narrow threshold level may lead to postnatal neurological impairment. To evaluate MeCP2 dosage effects, we generated Mecp2(WT_EGFP) transgenic (TG) mouse in which MeCP2 (endogenous plus TG) is mildly overexpressed (approximately 1.5×). The TG MeCP2(WT_EGFP) fusion protein is functionally active, as cross breeding of these mice with Mecp2 knockout mice led to alleviation of major phenotypes in the null mutant mice, including premature lethality. To characterize the Mecp2(WT_EGFP) mouse model, we performed an extensive battery of behavioral tests, which revealed that these mice manifest increased aggressiveness and higher pentylenetetrazole (PTZ)-induced seizure propensity. Evaluation of neuronal parameters revealed a reduction in the number of tertiary branching sites and increased spine density in Mecp2(WT_EGFP) transgenic (TG) neurons. Treatment of TG neurons with epileptogenic compound-PTZ led to a marked increase in amplitude and frequency of calcium spikes. Based on our ex vivo and in vivo data, we conclude that epileptic seizures are manifested as the first symptom when MeCP2 is mildly overexpressed in mice.
authors.affiliation: Institute of Human Genetics, Universitätsmedizin Göttingen, Göttingen, Germany.
authors.forename: Chiranjeevi
authors.initials: C
authors.lastname: Bodda
authors.forename: Martesa
authors.initials: M
authors.lastname: Tantra
authors.forename: Rustam
authors.initials: R
authors.lastname: Mollajew
authors.forename: Jayamuruga P
authors.initials: JP
authors.lastname: Arunachalam
authors.forename: Franco A
authors.initials: FA
authors.lastname: Laccone
authors.forename: Karolina
authors.initials: K
authors.lastname: Can
authors.forename: Albert
authors.initials: A
authors.lastname: Rosenberger
authors.forename: Sergej L
authors.initials: SL
authors.lastname: Mironov
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
authors.forename: Ashraf U
authors.initials: AU
authors.lastname: Mannan
mesh_terms: D000374:Aggression / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009483:Neuropsychological Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D002118:Calcium