title: Defects in brainstem neurons associated with breathing and motor function in the Mecp2R168X/Y mouse model of Rett syndrome.
abstract: Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder caused mostly by disruption of the MECP2 gene. Among several RTT-like mouse models, one of them is a strain of mice that carries an R168X point mutation in Mecp2 and resembles one of the most common RTT-causing mutations in humans. Although several behavioral defects have previously been found in the Mecp2R168X/Ymice, alterations in nerve cells remain unknown. Here we compare several behavioral and cellular outcomes between this Mecp2R168X/Ymodel and a widely used Mecp2Bird/Ymouse model. With lower body weight and shorter lifespan than their wild-type littermates, the Mecp2R168X/Ymice showed impairments of breathing and motor function. Thus we studied brainstem CO2-chemosensitive neurons and propriosensory cells that are associated with these two functions, respectively. Neurons in the locus coeruleus (LC) of both mutant strains showed defects in their intrinsic membrane properties, including changes in action potential morphology and excessive firing activity. Neurons in the mesencephalic trigeminal nucleus (Me5) of both strains displayed a higher firing response to depolarization than their wild-type littermates, likely attributable to a lower firing threshold. Because the increased excitability in LC and Me5 neurons tends to impact the excitation-inhibition balances in brainstem neuronal networks as well as their associated functions, it is likely that the defects in the intrinsic membrane properties of these brainstem neurons contribute to the breathing abnormalities and motor dysfunction. Furthermore, our results showing comparable phenotypical outcomes of Mecp2R168X/Ymice with Mecp2Bird/Ymice suggest that both strains are valid animal models for RTT research.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Johnson
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia.
authors.forename: Ningren
authors.initials: N
authors.lastname: Cui
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia.
authors.forename: Hao
authors.initials: H
authors.lastname: Xing
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia cjiang@gsu.edu.
authors.forename: Chun
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D008125:Locus Coeruleus / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D012119:Respiration; D015518:Rett Syndrome / Q000378:metabolism* / Q000473:pathology*
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2
keywords: Me5; Mecp2; R168X; Rett syndrome; breathing; electrophysiology; locus coeruleus