| First Author | Zhong W | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 30 | Pages | 18400-11 |
| PubMed ID | 25979331 | Mgi Jnum | J:224611 |
| Mgi Id | MGI:5688422 | Doi | 10.1074/jbc.M115.650465 |
| Citation | Zhong W, et al. (2015) Methyl CpG Binding Protein 2 Gene Disruption Augments Tonic Currents of gamma-Aminobutyric Acid Receptors in Locus Coeruleus Neurons: IMPACT ON NEURONAL EXCITABILITY AND BREATHING. J Biol Chem 290(30):18400-11 |
| abstractText | 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 mum GABA, the bicuculline-sensitive tonic currents were approximately 4-fold larger in Mecp2-null LC neurons than in the WT. Single-cell PCR analysis showed that the delta subunit, the principal subunit of extrasynaptic GABAARs, was present in LC neurons. Expression levels of the delta subunit were approximately 50% higher in Mecp2-null neurons than in the WT. Also increased in expression in Mecp2-null mice was another extrasynaptic GABAAR subunit, alpha6, by approximately 4-fold. The delta 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. |
