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

Abstract

Mice deficient in the transcription factor methyl-CpG-binding protein 2 (Mecp2), a mouse model of Rett syndrome, display reduced CO2 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 CO2. Here we determined the apnoeic threshold in heterozygous Mecp2-deficient female mice and examined the effects of blocking 5-HT reuptake on the CO2 response in Mecp2-null male mice. Studies were performed in B6.129P2(C)-Mecp2τm1.1Bird 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 CO2 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 CO2 chemosensitivity in null males. These mice were exposed sequentially to 1, 3 and 5% CO2. The percentage increase in minute ventilation in response to increased inspired CO2 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 CO2 exposure, in Mecp2−/y mice resulted in an improvement in CO2 chemosensitivity to wild-type levels. These results suggest that decreased 5-HT in Mecp2-deficient mice reduces CO2 chemosensitivity, and restoring 5-HT levels can reverse this effect.

Conditional depletion of methyl-CpG-binding protein 2 in astrocytes depresses the hypercapnic ventilatory response in mice

“…The magnitude of this reduced response in minute ventilation (62, 59, and 43% less than that of WT at 1, 3, and 5% inspired CO 2 , respectively) was similar to that observed in conditions of global MeCP2 deficiency (50,38, and 30%) (50), also reported in separate studies at 1, 2, and 3% inspired CO 2 (38,39, and 48%) (58). In addition, the extent of depression in the HCVR was comparable to that seen with either elimination or silencing of chemosensitive serotonin (5-HT) raphé neurons or removal of Phox2b-expressing neurons in the RTN, summarized in Table 1.…”

“…While the generally accepted view holds that response to CO 2 is a property of neurons, recent work has pointed to an important contribution from astrocytes (14,15,18,21,27). Respiratory CO 2 ventilatory response is significantly depressed in mice that lack or are deficient in the X-linked transcription factor methyl-CpG-binding protein 2 (MeCP2) (6,50,58). Mutations in this nuclear protein cause the neurological disorder Rett syndrome (RTT) (3).…”

Pathologic Aerophagia in Rett Syndrome

“…As noted by Chapleau et al, the most successful management of anxiety is the use of selective serotonin reuptake inhibitors [1]. Studies note lower serotonin levels in the hippocampus of MECP2 null mice compared to wild-type mice thus it is possible that adjusting serotonin levels might improve mood as well as carbon dioxide chemosensitivity in RS patients [2,7].…”

“…RS patients and male mice that are null for MECP2 display reduced levels of brain 5-HT, which is important for central chemosensitivity [7]. Moreover, mice deficient in MECP2 have also displayed reduced carbon dioxide (CO 2 ) chemosensitivity, which may contribute to breathing abnormalities [7].…”

“…RS patients and male mice that are null for MECP2 display reduced levels of brain 5-HT, which is important for central chemosensitivity [7]. Moreover, mice deficient in MECP2 have also displayed reduced carbon dioxide (CO 2 ) chemosensitivity, which may contribute to breathing abnormalities [7]. A study of serotonin function in male mice deficient in MECP2 noted that the use of an SSRI resulted in improved CO 2 chemosensitivity suggesting that an elevation of serotonin levels has a beneficial effect in breathing irregularities [7].…”