ArticleThe Journal of biological chemistry2015
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.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 26 citations in OpenAlex.
- Enhancement of hippocampal interneuron excitability by NMDA receptor positive allosteric modulation.The Journal of physiology · 2025Article
- Excitation and Inhibition Imbalance in Rett Syndrome.Frontiers in neuroscience · 2022Review
- Loss of MeCP2 increases GABA uptake by astrocytes to suppress tonic inhibition of CA1 pyramidal neurons.Journal of neurophysiology · 2021Article
- The antitussive cloperastine improves breathing abnormalities in a Rett Syndrome mouse model by blocking presynaptic GIRK channels and enhancing GABA release.Neuropharmacology · 2020Article
- An Astrocytic Influence on Impaired Tonic Inhibition in Hippocampal CA1 Pyramidal Neurons in a Mouse Model of Rett Syndrome.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Early alterations in a mouse model of Rett syndrome: the GABA developmental shift is abolished at birth.Scientific reports · 2019Article
- From Cannabinoids and Neurosteroids to Statins and the Ketogenic Diet: New Therapeutic Avenues in Rett Syndrome?Frontiers in neuroscience · 2019Review
- Common Ribs of Inhibitory Synaptic Dysfunction in the Umbrella of Neurodevelopmental Disorders.Frontiers in molecular neuroscience · 2018Review
- Defective GABAergic neurotransmission in the nucleus tractus solitarius in Mecp2-null mice, a model of Rett syndrome.Neurobiology of disease · 2018Article
- Suppression of Harmaline Tremor by Activation of an Extrasynaptic GABATremor and other hyperkinetic movements (New York, N.Y.) · 2018Article
- Breathing abnormalities in animal models of Rett syndrome a female neurogenetic disorder.Respiratory physiology & neurobiology · 2017Review
- Effects of early-life exposure to THIP on brainstem neuronal excitability in the Mecp2-null mouse model of Rett syndrome before and after drug withdrawal.Physiological reports · 2017Article
- Defects in brainstem neurons associated with breathing and motor function in the Mecp2R168X/Y mouse model of Rett syndrome.American journal of physiology. Cell physiology · 2016Article
- Neurobiologically-based treatments in Rett syndrome: opportunities and challenges.Expert opinion on orphan drugs · 2016Review
- An optogenetic mouse model of rett syndrome targeting on catecholaminergic neurons.Journal of neuroscience research · 2016Article
- Characterization of Rett Syndrome-like phenotypes in Mecp2-knockout rats.Journal of neurodevelopmental disorders · 2016Article
- Effects of early-life exposure to THIP on phenotype development in a mouse model of Rett syndrome.Journal of neurodevelopmental disorders · 2016Article
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9 authors at 1 institution in 1 country.
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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.
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