Alteration of monoaminergic systems in the caudal medulla and its possible link to diurnal increase of apnea in a mouse model of Rett syndrome.

Abstract

Purpose: Methyl-CpG binding protein 2 (MeCP2)-deficient (Mecp2^-/y) mice exhibit apneas that resemble respiratory abnormalities observed in Rett syndrome (RTT) patients. The present study aimed to clarify whether Mecp2^-/y mice show diurnal variations in apnea as seen in RTT and how the MeCP2 deficiency affects monoaminergic systems that control breathing.

Methods: In 7-week-old Mecp2^-/y mice, 24 h variation of apnea and effects of milnacipran, a serotonin/noradrenaline reuptake inhibitor, on the apnea were evaluated. The number of vesicular monoamine transporter 2 (VMAT2)-immunoreactive puncta in the caudal medulla was counted. Further, the effects of valproate (VPA) on the expression of tyrosine hydroxylase (TH) mRNA in the ventrolateral medulla of mice were assessed by RT-qPCR.

Results: Apnea occurred more frequently during the light phase under a 12:12 h light/dark environment in Mecp2^-/y mice and milnacipran reduced apnea during the light phase but not during the dark phase. The number of VMAT2-immunoreactive puncta was reduced in Mecp2^-/y mice. VPA treatment significantly increased TH mRNA expression in Mecp2^-/y mice.

Conclusion: Alteration of monoaminergic systems in the caudal medulla of Mecp2^-/y mice is potentially relevant to the light-sensitive diurnal increase of apnea, and an improvement in monoaminergic neurotransmission can ameliorate the diurnal increase of apnea in Mecp2^-/y mice.