Degraded neural and behavioral processing of speech sounds in a rat model of Rett syndrome

Abstract

Individuals with Rett syndrome have greatly impaired speech and language abilities. Auditory brainstem responses to sounds are normal, but cortical responses are highly abnormal. In this study, we used the novel rat Mecp2 knockout model of Rett syndrome to document the neural and behavioral processing of speech sounds. We hypothesized that both speech discrimination ability and the neural response to speech sounds would be impaired in Mecp2 rats. We expected that extensive speech training would improve speech discrimination ability and the cortical response to speech sounds. Our results reveal that speech responses across all four auditory cortex fields of Mecp2 rats were hyperexcitable, responded slower, and were less able to follow rapidly presented sounds. While Mecp2 rats could accurately perform consonant and vowel discrimination tasks in quiet, they were significantly impaired at speech sound discrimination in background noise. Extensive speech training improved discrimination ability. Training shifted cortical responses in both Mecp2 and control rats to favor the onset of speech sounds. While training increased the response to low frequency sounds in control rats, the opposite occurred in Mecp2 rats. Although neural coding and plasticity are abnormal in the rat model of Rett syndrome, extensive therapy appears to be effective. These findings may help to explain some aspects of communication deficits in Rett syndrome and suggest that extensive rehabilitation therapy might prove beneficial.

Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome

“…Furthermore, because regression in RTT may also coincide with the loss of speech, it may be informative to determine whether the type and nature of ultrasonic vocalizations (USV) emitted by female Mecp2 ZFN/+  rats, or other aspects of communication, change over time. Although we did not find differences in the total number of USV emitted by juvenile female Mecp2 ZFN/+  rats during direct social interaction tests (data not shown), a recent study of symptomatic 5-11 month old female Mecp2 ZFN/+  rats found alterations in speech processing (80), suggesting that communication deficits, in a broader context, may be affected in this model.…”

Shank3‐deficient rats exhibit degraded cortical responses to sound

“…Severe auditory cortex deficits have also been observed in the rodent Fmr1 knockout model of fragile X syndrome, the rodent valproic acid model of autism, and the rat Mecp2 knockout model of Rett syndrome (Gandal et al, 2010; Liao et al, 2012; Kim et al, 2013; Engineer et al, 2014a, 2014c, 2015a; Anomal et al, 2015). The auditory cortex responses observed in the Shank3 heterozygous rat model are weaker, which is consistent with other rat models of ASD.…”

“…Individuals with autism and genetic disorders, such as Rett syndrome, commonly exhibit receptive language deficits and cortical responses that are both weaker and slower [Bader, Witt-Engerstr€ om, & Hagberg, 1989;Stach, Stoner, Smith, & Jerger, 1994;Stauder, Smeets, van Mil, & Curfs, 2006;Gandal et al, 2010;Roberts et al, 2010]. Severe auditory cortex deficits have also been observed in the rodent Fmr1 knockout model of fragile X syndrome, the rodent valproic acid model of autism, and the rat Mecp2 knockout model of Rett syndrome [Gandal et al, 2010;Liao et al, 2012;Kim et al, 2013;Engineer et al, 2014aEngineer et al, , 2014cEngineer et al, , 2015aAnomal et al, 2015]. The auditory cortex responses observed in the Shank3 heterozygous rat model are weaker, which is consistent with other rat models of ASD.…”

“…In an effort to identify whether sensory processing abnormalities could contribute to the receptive language problems observed in this population, we assessed the neural response characteristics to sounds in multiple auditory cortical fields in the novel Shank3 genetically modified rat model. We hypothesized that the auditory cortex response to sounds would be altered, as seen in other rodent models of disorders that include receptive language deficits (Gandal et al, 2010; Liao et al, 2012; Kim et al, 2013; Centanni et al, 2014a, 2016, Engineer et al, 2014a, 2014c, 2015a). …”

Temporal plasticity in auditory cortex improves neural discrimination of speech sounds

“…This finding is paralleled in rodents; rats that were trained to use the repetition rate of noise pulses in order to find a target location exhibited enhanced A1 responses to rapid stimuli as well as stronger phase-locked responses [7]. Auditory training also greatly benefits rat models of disorders, such as autism or dyslexia [26,50]. Rats prenatally exposed to valproic acid are a well-studied autism model that exhibit significantly weaker and less synchronized responses to rapidly presented stimuli [51].…”