Methyl-CpG binding-protein 2 function in cholinergic neurons mediates cardiac arrhythmogenesis

Area of Science:

• Neuroscience
• Cardiology
• Genetics

Background:

• Rett Syndrome (RTT) is a neurodevelopmental disorder caused by MECP2 mutations.
• RTT is associated with autonomic nervous system (ANS) dysfunction, including cardiac abnormalities and hypothermia.
• Sudden unexpected death occurs in 25% of RTT cases, often linked to cardiac events.

Purpose of the Study:

• To investigate the role of cardiac rhythm abnormalities in sudden death in RTT.
• To explore the function of MECP2 in the parasympathetic nervous system's control of cardiac function.
• To identify potential therapeutic targets for preventing sudden death in RTT.

Main Methods:

• Characterized cardiac rhythm in mice lacking Mecp2 function.
• Administered atropine to assess the role of parasympathetic tone.
• Generated and analyzed mice with selective MeCP2 deletion or restoration in cholinergic neurons (MeCP2 ChAT KO).

Main Results:

• Mecp2-deficient mice exhibited spontaneous cardiac arrhythmias (bradycardia, AV block, PVCs, VT) and increased heart rate variability.
• Cardiac arrhythmias and conduction block were associated with death in mutant mice.
• Atropine treatment reduced cardiac arrhythmias, suggesting overactive parasympathetic tone.
• Selective deletion of MeCP2 in cholinergic neurons recapitulated RTT-like phenotypes (cardiac, thermoregulation, survival).
• Restoring MeCP2 in cholinergic neurons rescued these phenotypes.

Conclusions:

• MeCP2 in cholinergic neurons is essential for normal autonomic cardiac control, thermoregulation, and survival.
• Overactive parasympathetic system contributes to cardiac dysfunction and sudden death in RTT.
• Targeting the parasympathetic system may offer a therapeutic strategy for RTT.