Increasing brain serotonin corrects CO₂ chemosensitivity in methyl‐CpG‐binding protein 2 (Mecp2)‐deficient mice

Abstract

New Findings What is the central question of this study? Mice deficient in methyl‐CpG‐binding protein 2 (Mecp2; a model of Rett syndrome) display reduced CO 2 chemosensitivity, which may contribute to their breathing abnormalities. Patients and mice show reduced levels of brain 5‐HT, which is important in central chemosensitivity. It is not known whether increasing 5‐HT in this mouse model would improve their respiratory response to CO 2 . What is the main finding and its importance? We show, for the first time, that females heterozygous for the Mecp2 mutation have a higher hypocapnic threshold for apnoeas versus wild‐type mice and that increasing 5‐HT in Mecp2 ‐null males, with citalopram, can correct CO 2 chemosensitivity, a finding that may be important clinically. Mice deficient in the transcription factor methyl‐CpG‐binding protein 2 (Mecp2), a mouse model of Rett syndrome, display reduced CO 2 chemosensitivity, which may contribute to their breathing abnormalities. In addition, patients with Rett syndrome and male mice that are null for Mecp2 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 2 . Here we determined the apnoeic threshold in heterozygous Mecp2‐deficient female mice and examined the effects of blocking 5‐HT reuptake on the CO 2 response in Mecp2 ‐null male mice. Studies were performed in B6.129P2(C)‐ Mecp2 τm1.1Bird null males and heterozygous females. In an in situ preparation, seven of eight Mecp2‐deficient heterozygous females showed arrest of phrenic nerve activity when arterial CO 2 was lowered to 3%, whereas the wild‐types maintained phrenic nerve amplitude at 53 ± 3% of maximal. In vivo plethysmography studies were used to determine CO 2 chemosensitivity in null males. These mice were exposed sequentially to 1, 3 and 5% CO 2 . The percentage increase in minute ventilation in response to increased inspired CO 2 was less in Mecp2 −/y than in Mecp2 +/y mice. Pretreatment with citalopram, a selective 5‐HT reuptake inhibitor (2.5 mg kg −1 i.p. ), 40 min prior to CO 2 exposure, in Mecp2 −/y mice resulted in an improvement in CO 2 chemosensitivity to wild‐type levels. These results suggest that decreased 5‐HT in Mecp2‐deficient mice reduces CO 2 chemosensitivity, and restoring 5‐HT levels can reverse this effect.