title: Effects of chronic exposure to low dose THIP on brainstem neuronal excitability in mouse models of Rett syndrome: Evidence from symptomatic females.
abstract: Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations of the MECP2 gene, affecting predominantly females. One of the characteristic features of the disease is defective brainstem autonomic function. In Mecp2-/Ymice, several groups of brainstem neurons are overly excitable, which causes destabilization of neuronal networks for the autonomic control. We have previously shown that the extrasynaptic GABAAreceptor agonist THIP relieves many RTT-like symptoms in Mecp2-/Ymice. Although neuronal activity is inhibited by acute THIP exposure, how a chronic treatment affects neuronal excitability remains elusive. Thus, we performed studies to address whether increased excitability occurs in brainstem neurons of female Mecp2+/-mice, how the MeCP expression affects the neuronal excitability, and whether chronic THIP exposure improves the neuronal hyperexcitability. Symptomatic Mecp2+/-(sMecp2+/-) female mice were identified with a two-step screening system. Whole-cell recording was performed in brain slices after a prior exposure of the sMecp2+/-mice to a 5-week low-dose THIP. Neurons in the locus coeruleus (LC) and the mesencephalic trigeminal nucleus (Me5) showed excessive firing activity in the sMecp2+/-mice. THIP pretreatment reduced the hyperexcitability of both LC and Me5 neurons in the sMecp2+/-mice, to a similar level as their counterparts in Mecp2-/Ymice. In identified LC neurons, the hyperexcitability appeared to be determined by not only the MeCP2 expression, but also their environmental cues. The alleviation of LC neuronal hyperexcitability seems to benefit brainstem autonomic function as THIP also improved breathing abnormalities of these sMecp2+/-mice.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Biology, Georgia State University, Atlanta, USA.
authors.forename: Christopher Mychal
authors.initials: CM
authors.lastname: Johnson
authors.affiliation: Department of Biology, Georgia State University, Atlanta, USA.
authors.forename: Ningren
authors.initials: N
authors.lastname: Cui
authors.affiliation: Department of Biology, Georgia State University, Atlanta, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Xing
authors.affiliation: Department of Biology, Georgia State University, Atlanta, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Biology, Georgia State University, Atlanta, USA. Electronic address: cjiang@gsu.edu.
authors.forename: Chun
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D011897:Random Allocation; D015518:Rett Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D046509:Tissue Culture Techniques
chemical_list: D018755:GABA Agonists; D007555:Isoxazoles; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; C015542:gaboxadol
keywords: Electrophysiology; Female mouse model; Locus coeruleus; Mecp2; Neuronal excitability; THIP