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

A recent study showed that CO2 chemosensitivity is depressed in male mice with deletion of the transcription factor methyl-CpG-binding protein 2 (Mecp2; Zhang et al. 2011). MECP2 is mutated in the autism spectrum disorder Rett syndrome (RTT), and the phenotype includes abnormal respiration characterized by hyperventilation followed by apnoea (Southall et al. 1988; Smeets et al. 2006). An elevated CO2 threshold in RTT would contribute to apnoea, and significant hypocapnia has been reported in affected individuals (Southall et al. 1988). Zhang and co-authors reported a blunted CO2 response, relative to wild-type (WT) mice, at 1, 2 and 3% CO2, but no difference at 6 and 9%. Earlier reports had not shown a difference in the respiratory response to CO2 between Mecp2-deficient and WT mice (Bissonnette & Knopp, 2006; Voituron et al. 2009). Bissonnette & Knopp (2006) used CO2 concentrations of 3, 5 and 7%, with the balance being oxygen. The hyperoxia would blunt contributions from peripheral chemoreceptors that are important to the integrated CO2 response (Forster et al. 2000; Blain et al. 2010; Ramanantsoa et al. 2011). Voituron and co-authors (2009) used a single CO2 level of 4% in air. In view of the findings of Zhang et al. (2011), which showed no difference in response to CO2 at higher levels (i.e. 6 and 9%), this single 4% exposure may have failed to show the depressed respiratory response in Mecp2-null mice that is present at 1 and 3% CO2. Subjects with RTT and mouse models have deficits in serotonin (5-HT). 5-Hydroxyindoleacetic acid levels are low in the cerebrospinal fluid of individuals with RTT (Samaco et al. 2009). Brain 5-HT levels in Mecp2-null males, while initially normal, are depressed at postnatal day 42 and thereafter (Ide et al. 2005; Viemari et al. 2005; Panayotis et al. 2011). In addition, a recent study has shown that a serotonin 1a receptor agonist reduces apnoea, corrects the irregular breathing pattern and prolongs survival in Mecp2-null males (Abdala et al. 2010). The importance of 5-HT in CO2 chemosensitivity is well documented (reviewed by Hilaire et al. 2010; Hodges & Richerson, 2010a,b). The goal of the present study was to determine whether increasing brain 5-HT will correct the blunted CO2 response in Mecp2-deficient mice.