{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T02:56:32Z","timestamp":1776567392119,"version":"3.51.2"},"reference-count":75,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,12,14]],"date-time":"2015-12-14T00:00:00Z","timestamp":1450051200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Life threatening breathing irregularity and central apnoeas are highly prevalent in children suffering from Rett syndrome.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Abnormalities in inhibitory synaptic transmission have been associated with the physiopathology of this syndrome, and may underlie the respiratory disorder.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In a mouse model of Rett syndrome, GABAergic terminal projections are markedly reduced in the K\u00f6lliker\u2013Fuse nucleus (KF) in the dorsolateral pons, an important centre for control of respiratory rhythm regularity.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Administration of a drug that augments endogenous GABA localized to this region of the pons reduced the incidence of apnoea and the respiratory irregularity of Rett female mice. Conversely, the respiratory disorder was recapitulated by blocking GABAergic transmission in the KF area of healthy rats.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This study helps us understand the mechanism for generation of respiratory abnormality in Rett syndrome, pinpoints a brain site responsible and provides a clear anatomical target for the development of a translatable drug treatment.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Central apnoeas and respiratory irregularity are a common feature in Rett syndrome (RTT), a neurodevelopmental disorder most often caused by mutations in the methyl\u2010CpG\u2010binding protein 2 gene (<jats:italic>MECP2<\/jats:italic>). We used a MECP2 deficient mouse model of RTT as a strategy to obtain insights into the neurobiology of the disease and into mechanisms essential for respiratory rhythmicity during normal breathing. Previously, we showed that, systemic administration of a GABA reuptake blocker in MECP2 deficient mice markedly reduced the occurrence of central apnoeas. Further, we found that, during central apnoeas, post\u2010inspiratory drive (adductor motor) to the upper airways was enhanced in amplitude and duration in <jats:italic>Mecp2<\/jats:italic> heterozygous female mice. Since the pontine K\u00f6lliker\u2013Fuse area (KF) drives post\u2010inspiration, suppresses inspiration, and can reset the respiratory oscillator phase, we hypothesized that synaptic inhibition in this area is essential for respiratory rhythm regularity. In this study, we found that: (i) <jats:italic>Mecp2<\/jats:italic> heterozygous mice showed deficiency of GABA perisomatic bouton\u2010like puncta and processes in the KF nucleus; (ii) blockade of GABA reuptake in the KF of RTT mice reduced breathing irregularity; (iii) conversely, blockade of GABA<jats:sub>A<\/jats:sub> receptors in the KF of healthy rats mimicked the RTT respiratory phenotype of recurrent central apnoeas and prolonged post\u2010inspiratory activity. Our results show that reductions in synaptic inhibition within the KF induce rhythm irregularity whereas boosting GABA transmission reduces respiratory arrhythmia in a murine model of RTT. Our data suggest that manipulation of synaptic inhibition in KF may be a clinically important strategy for alleviating the life threatening respiratory disorders in RTT.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp270966","type":"journal-article","created":{"date-parts":[[2015,10,28]],"date-time":"2015-10-28T07:44:30Z","timestamp":1446018270000},"page":"223-237","source":"Crossref","is-referenced-by-count":54,"title":["Deficiency of GABAergic synaptic inhibition in the K\u00f6lliker\u2013Fuse area underlies respiratory dysrhythmia in a mouse model of Rett syndrome"],"prefix":"10.1113","volume":"594","author":[{"given":"Ana Paula","family":"Abdala","sequence":"first","affiliation":[{"name":"School of Physiology and Pharmacology, Medical Sciences Building University of Bristol  Bristol BS8 1TD UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie A.","family":"Toward","sequence":"additional","affiliation":[{"name":"School of Physiology and Pharmacology, Medical Sciences Building University of Bristol  Bristol BS8 1TD UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathias","family":"Dutschmann","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health University of Melbourne  Gate 11, Royal Parade Victoria 3052 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"Bissonnette","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Oregon Health and Science University  Portland OR 97239 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julian F. 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