Variability-dominated auditory cortical dysfunction and targeted VNS modulation in a Mecp2^+/- model of Rett syndrome

Rett syndrome is a neurodevelopmental disorder caused by mutations in the X-linked transcriptional regulator MECP2, which causes widespread abnormalities in cortical network activity and sensory processing. In rodent models, Mecp2^+/- rats recapitulate key clinical features of Rett syndrome, including disrupted auditory cortical responses and impaired spike timing fidelity. Given its potential to normalize abnormal cortical activity, vagus nerve stimulation (VNS) may offer a promising therapeutic approach. This study examined auditory local field potential (LFP) responses in Mecp2^+/- rats and assesses the modulatory effects of VNS.

Auditory cortical LFPs were recorded in response to speech, noise, and tone stimuli in Mecp2^+/- rats, VNS-treated Mecp2^+/- rats, and wild-type littermates. LFP component latency, amplitude, trial-to-trial variability, and oscillatory band power were quantitatively analyzed across groups.

Mecp2^+/- rats were characterized by delayed and weakened LFP responses, widespread increases in trial-to-trial variability of latency, amplitude, and power, and stimulus-dependent changes in spectral power, with the most pronounced abnormalities for speech, followed by tones and then noise. VNS partially normalized these abnormalities by improving speech-evoked latency and variability and reducing noise-evoked power variability. However, tone-evoked responses were largely unchanged with VNS, indicating a selective rescue of specific components and stimulus classes rather than a global restoration of auditory function. These findings demonstrate robust auditory cortical processing deficits in a preclinical model of Rett syndrome and highlight the potential of VNS to partially restore cortical function. The results support further development of targeted neuromodulatory interventions to ameliorate sensory processing abnormalities in Rett syndrome.