Altered oscillatory coupling reflects possible inhibitory interneuron dysfunction in Rett syndrome

Area of Science:

• Neuroscience
• Computational Neuroscience
• Genetics

Background:

• Rett syndrome, a neurodevelopmental disorder caused by MECP2 gene variants, results in cognitive impairments.
• Understanding large-scale brain dynamics via neural oscillations is crucial for studying Rett syndrome.
• Phase-amplitude coupling (PAC) is a key cross-frequency interaction for information integration, potentially revealing neural dysfunction.

Purpose of the Study:

• To investigate alterations in phase-amplitude coupling (PAC) in Rett syndrome.
• To explore the underlying cellular and circuit-level mechanisms of PAC changes.
• To identify potential biomarkers and therapeutic targets for Rett syndrome.

Main Methods:

• Recorded resting-state EEG from individuals with Rett syndrome and controls.
• Quantified PAC strength (modulation index) and phase bias.
• Modeled a biophysically-constrained cortical network to identify mechanisms.

Main Results:

• Significantly stronger PAC in Rett syndrome across widespread cortical regions and frequency pairs (e.g., theta-gamma, alpha-gamma).
• Increased theta-gamma and alpha-gamma coupling observed in anterior, posterior, and whole-brain regions.
• Biophysically constrained modeling indicated reduced VIP-expressing interneuron activity could explain observed PAC alterations.

Conclusions:

• Identified altered awake-state PAC in Rett syndrome, mechanistically linked to VIP+ interneuron dysfunction.
• Elevated PAC may serve as a biomarker for cortical dysfunction and bridge neural circuitry to EEG signatures.
• Results suggest VIP+ interneurons as a target for novel therapeutic interventions in Rett syndrome.