title: Methyl CpG Binding Protein 2 Gene Disruption Augments Tonic Currents of γ-Aminobutyric Acid Receptors in Locus Coeruleus Neurons: IMPACT ON NEURONAL EXCITABILITY AND BREATHING.
abstract: People with Rett syndrome and mouse models show autonomic dysfunction involving the brain stem locus coeruleus (LC). Neurons in the LC of Mecp2-null mice are overly excited, likely resulting from a defect in neuronal intrinsic membrane properties and a deficiency in GABA synaptic inhibition. In addition to the synaptic GABA receptors, there is a group of GABAA receptors (GABAARs) that is located extrasynaptically and mediates tonic inhibition. Here we show evidence for augmentation of the extrasynaptic GABAARs in Mecp2-null mice. In brain slices, exposure of LC neurons to GABAAR agonists increased tonic currents that were blocked by GABAAR antagonists. With 10 μm GABA, the bicuculline-sensitive tonic currents were ∼4-fold larger in Mecp2-null LC neurons than in the WT. Single-cell PCR analysis showed that the δ subunit, the principal subunit of extrasynaptic GABAARs, was present in LC neurons. Expression levels of the δ subunit were ∼50% higher in Mecp2-null neurons than in the WT. Also increased in expression in Mecp2-null mice was another extrasynaptic GABAAR subunit, α6, by ∼4-fold. The δ subunit-selective agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride and 4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl]]benzamide activated the tonic GABAA currents in LC neurons and reduced neuronal excitability to a greater degree in Mecp2-null mice than in the WT. Consistent with these findings, in vivo application of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride alleviated breathing abnormalities of conscious Mecp2-null mice. These results suggest that extrasynaptic GABAARs seem to be augmented with Mecp2 disruption, which may be a compensatory response to the deficiency in GABAergic synaptic inhibition and allows control of neuronal excitability and breathing abnormalities.
authors.affiliation: From the Department of Biology, Georgia State University, Atlanta, Georgia 30303.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhong
authors.affiliation: From the Department of Biology, Georgia State University, Atlanta, Georgia 30303.
authors.forename: Ningren
authors.initials: N
authors.lastname: Cui
authors.affiliation: From the Department of Biology, Georgia State University, Atlanta, Georgia 30303.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: From the Department of Biology, Georgia State University, Atlanta, Georgia 30303.
authors.forename: Max F
authors.initials: MF
authors.lastname: Oginsky
authors.affiliation: From the Department of Biology, Georgia State University, Atlanta, Georgia 30303.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the Department of Biology, Georgia State University, Atlanta, Georgia 30303.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: From the Department of Biology, Georgia State University, Atlanta, Georgia 30303.
authors.forename: Brian
authors.initials: B
authors.lastname: Bondy
authors.affiliation: From the Department of Biology, Georgia State University, Atlanta, Georgia 30303.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Johnson
authors.affiliation: From the Department of Biology, Georgia State University, Atlanta, Georgia 30303 cjiang@gsu.edu.
authors.forename: Chun
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000008:administration & dosage; D018755:GABA Agonists / Q000008:administration & dosage; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage; D008125:Locus Coeruleus / Q000378:metabolism / Q000503:physiopathology; D051783:Methyl-CpG-Binding Protein 2 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018079:Receptors, GABA / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012119:Respiration / Q000235:genetics; D015518:Rett Syndrome / Q000235:genetics* / Q000503:physiopathology; D059010:Single-Cell Analysis; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D018755:GABA Agonists; D007555:Isoxazoles; D051783:Methyl-CpG-Binding Protein 2; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C015542:gaboxadol; D001640:Bicuculline
keywords: GABA receptor; Rett syndrome; THIP; autism; breathing abnormalities; electrophysiology; locus coeruleus; pharmacology; respiration; tonic GABAA currents