Increasing brain serotonin corrects CO2 chemosensitivity in methyl‐CpG‐binding protein 2 (Mecp2)‐deficient mice. Issue 3 (20th February 2013)

• Record Type: Journal Article
• Authors: Toward, Marie A.; Abdala, Ana P.; Knopp, Sharon J.; Paton, Julian F. R.; Bissonnette, John M.
• Is Part Of: Experimental physiology. Volume 98:Issue 3(2013:Mar.)
• Page Start: 842
• Page End: 849
• Publication Date: 2013-02-20
• Subjects: Physiology, Experimental -- Periodicals; 571.0724
• DOI: 10.1113/expphysiol.2012.069872
• Languages: English
• ISSNs: 0958-0670

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Mice deficient in the transcription factor methyl‐CpG‐binding protein 2 (Mecp2), a mouse model of Rett syndrome, display reduced CO<sub>2</sub> chemosensitivity, which may contribute to their breathing abnormalities. In addition, patients with Rett syndrome and male mice that are null for <italic>Mecp2</italic> show reduced levels of brain serotonin (5‐HT). Serotonin is known to play a role in central chemosensitivity, and we hypothesized that increasing the availability of 5‐HT in this mouse model would improve their respiratory response to CO<sub>2</sub>. Here we determined the apnoeic threshold in heterozygous Mecp2‐deficient female mice and examined the effects of blocking 5‐HT reuptake on the CO<sub>2</sub> response in <italic>Mecp2</italic>‐null male mice. Studies were performed in B6.129P2(C)‐<italic>Mecp2<sup>τm1.1Bird</sup></italic> null males and heterozygous females. In an <italic>in situ</italic> preparation, seven of eight Mecp2‐deficient heterozygous females showed arrest of phrenic nerve activity when arterial CO<sub>2</sub> was lowered to 3%, whereas the wild‐types maintained phrenic nerve amplitude at 53 ± 3% of maximal. <italic>In vivo</italic> plethysmography studies were used to determine CO<sub>2</sub> chemosensitivity in null males. These mice were exposed sequentially to 1, 3 and 5% CO<sub>2</sub>. The percentage increase in minute ventilation in response to increased inspired CO<sub>2</sub> was less in <italic>Mecp2</italic><sup>−/y</sup> than in <italic>Mecp2</italic><sup>+/y</sup> mice. Pretreatment with citalopram, a selective 5‐HT reuptake inhibitor (2.5 mg kg<sup>−1</sup> <sc>i.p.</sc>), 40 min prior to CO<sub>2</sub> exposure, in <italic>Mecp2</italic><sup>−/y</sup> mice resulted in an improvement in CO<sub>2</sub> chemosensitivity to wild‐type levels. These results suggest that decreased 5‐HT in Mecp2‐deficient mice reduces CO<sub>2</sub> chemosensitivity, and restoring 5‐HT levels can reverse this effect.</p> </abstract>