MeCP2+/- mouse model of RTT reproduces auditory phenotypes associated with Rett syndrome and replicate select EEG endophenotypes of autism spectrum disorder

Abstract

Impairments in cortical sensory processing have been demonstrated in Rett syndrome (RTT) and Autism Spectrum Disorders (ASD) and are thought to contribute to high-order phenotypic deficits. However, underlying pathophysiological mechanisms for these abnormalities are unknown. This study investigated auditory sensory processing in a mouse model of RTT with a heterozygous loss of MeCP2 function. Cortical abnormalities in a number of neuropsychiatric disorders, including ASD are reflected in auditory evoked potentials and fields measured by EEG and MEG. One of these abnormalities, increased latency of cortically sourced components, is associated with language and developmental delay in autism. Additionally, gamma-band abnormalities have recently been identified as an endophenotype of idiopathic autism. Both of these cortical abnormalities are potential clinical endpoints for assessing treatment. While ascribing similar mechanisms of idiopathic ASD to Rett syndrome (RTT) has been controversial, we sought to determine if mouse models of RTT replicate these intermediate phenotypes. Mice heterozygous for the null mutations of the gene MeCP2, were implanted for EEG. In response to auditory stimulation, these mice recapitulated specific latency differences as well as select gamma and beta band abnormalities associated with ASD. MeCP2 disruption is the predominant cause of RTT, and reductions in MeCP2 expression predominate in ASD. This work further suggests a common cortical pathophysiology for RTT and ASD, and indicates that the MeCP2+/- model may be useful for preclinical development targeting specific cortical processing abnormalities in RTT with potential relevance to ASD.

Copyright © 2012 Elsevier Inc. All rights reserved.

Figures

Figure 1. Abnormal sensory evoked potentials found in MeCP2+/− mice

(A) Grand average of auditory evoked components from MeCP2+/− mice (gray) and wildtype female (black) littermates. In both types, a consistent P1, N1 and P2 pattern was generated. Note the increased N1 amplitude and delayed P2 latency in the MeCP2+/− mice. Inset of grand average auditory brain stem response (ABR) show that there was no significant difference in Grand-average visual evoked response in WT and MeCP2+/− mice. These mice show a similarly increased N1 amplitude upon visual stimulation, but no change in component latencies (B). In both auditory and visual response plots, dark bands on the time-axis indicate contiguous significant group time point differences. Notably, both types of stimulation yield significant slow wave differences in MeCP2+/− mice. Group differences for specific component amplitudes are shown for (C) auditory and (D) visual responses for MeCP2+/− mice (grey) and WT littermates (black). (E) P2 latency is shown for visual and auditory experiments. MeCP2+/− showed P2 latency prolongation in auditory, but not visual, evoked responses. Figures show mean +/− SEM, * p < 0.05.

Figure 2. Auditory stimulus associated changes found in EEG gamma and beta bands

(A) Time-frequency plots show similar patterns of early (0–100) increases in power increased from baseline in all frequency components (red; reduction at 60 Hz due to notch filter), followed by a return towards baseline (green) and in some areas a reduction in power (blue). For temporal comparison ERPs are drawn above panels. (B) Subtraction of the WT time-frequency responses reveals a number of significant time-differences following the evoked responses. These appear limited to gamma and beta ranges, illustrated by either a white line (area contained showing P<0.05, corrected for multiple comparisons) or a black line (P<0.01, corrected for multiple comparisons). (C, D) As phase locking deficits have been reported in a number psychiatric disorders, we show a plot of the phase-locking factor (i.e., intertrial coherence, ITC) between trials over the same time-frequency bins. Surprisingly ITC was increased at early time points (<100 ms) in the gamma-band indicating hyper-synchronous activity in MeCP2+/− mice.