Vagus Nerve Stimulation Paired With Tones Alters the Auditory Cortex Proteome in a Rat Model of Rett Syndrome

ABSTRACT Rett syndrome is a neurodevelopmental disorder caused by an X‐linked mutation of the MeCP2 gene. Individuals with Rett syndrome, as well as rodent models of this disorder, demonstrate abnormal cortical responses to sound, which impair auditory discrimination ability. Vagus nerve stimulation (VNS) paired with tones has been shown to drive robust changes in the auditory cortex physiology of Mecp2 +/− rats and has the potential to improve the communication abilities of individuals with Rett syndrome. The aim of this study was to describe the proteomic differences present in the auditory cortex of the Mecp2 +/− rat model of Rett syndrome, as well as the molecular effect of VNS paired with tones. This study used global proteomic analysis of auditory cortex tissue taken from Mecp2 +/− rats exposed to VNS paired with tones compared to untreated Mecp2 +/− rats and wild‐type (WT) littermate controls with no VNS exposure. Our results demonstrate dysregulation of mitochondrial and synaptic proteins in the Mecp2 +/− rat auditory cortex. In addition, we show that VNS‐tone pairing induces significant alterations to the auditory cortex proteome of Mecp2 +/− rats by changing the expression of proteins involved in regulating synaptic vesicles and synaptic transmission. This work provides evidence of key mechanisms that may drive auditory processing dysfunction in Rett syndrome and demonstrates that VNS‐tone pairing is sufficient to alter protein expression in the auditory cortex.