Early neural dysfunction reflected in degraded auditory cortex responses in pre-regression heterozygous Mecp2 rats

Abstract

Rett syndrome, a genetic disorder caused by mutations in the X-linked Mecp2 gene, is characterized by typical early development followed by rapid developmental regression between 6 and 18 months of age. Affected individuals exhibit seizures, cognitive impairments, motor deficits, and difficulties in speech-language processing. Post-regression rodent models of Rett syndrome have been observed to follow similar regression, presenting sensory processing difficulties during auditory discrimination tasks, as well as degraded auditory cortical responses. However, little is known about the auditory processing prior to the onset of regression symptoms. This study documents primary auditory cortex responses to sounds in pre-regression heterozygous Mecp2 rats compared to age-matched wild-type controls. Pre-regression Mecp2 rats exhibited weaker and delayed cortical responses to speech sounds, alterations in the temporal processing of rapidly presented sounds, and an overrepresentation of high-frequency tones in conjunction with a reduction in the cortical representation of low-frequency tones. Despite these impairments, pre-regression Mecp2 rats demonstrated intact neural classifier performance for consonant discrimination, which is consistent with the high accuracy these pre-regression Mecp2 rats exhibit for a behavioral consonant discrimination task. These findings reveal that cortical deficits in Mecp2 rats emerge before behavioral regression. Insights derived from this study expand upon the current understanding of the progression of sensory processing deficits in Rett syndrome and other neurodevelopmental disorders and lay the groundwork for the development of therapeutics for this population.