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

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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.

Highlights

►We assayed sensory evoked potentials in a female mouse model of Rett syndrome. ►Auditory evoked potentials demonstrated increased N1 and increased P2 latency. ►Specific abnormalities were also found in gamma-band responses. ►These novel findings demonstrated a selective reproduction of ASD biomarkers.

Introduction

Event-related magnetoencephalography (MEG) and electroencephalography (EEG) studies of auditory and language processing have identified intermediate phenotypes associated with autism spectrum disorders (ASD) and abnormal responses in Rett syndrome (RTT) (Bader et al., 1989, Badr et al., 1987, Kalmanchey, 1990, Oram Cardy et al., 2008, Roberts et al., 2008, Stach et al., 1994). In autism, delayed middle latency components of the auditory-evoked response have been observed in the cortex (superior temporal gyrus) and have been linked to higher-order language impairments (Roberts et al., 2011). Likewise, abnormalities in cortical gamma-band (30–80 Hz) synchrony which have been observed in ASD, are thought to reflect deficits in excitatory–inhibitory balance (Gandal et al., 2010, Rojas et al., 2008, Wilson et al., 2007). Fewer and a less conclusive set or studies have been performed in girls with RTT (Kalmanchey, 1990) (Stach et al., 1994, Yamanouchi et al., 1993). The relative lack of preclinical studies investigating these auditory response deficits limits our ability to test for relationships between intermediate clinical phenotypes and neuronal circuit abnormalities in RTT.

Rett is a unique disorder, but shares proposed mechanistic and core symptoms of autism. In contrast to the complex genetic etiology of idiopathic ASD, RTT has a clear monogenetic basis with mutations in the X-linked gene MeCP2 occurring in approximately 90% of patients with RTT. Nevertheless, RTT is characterized by developmental regression, similar to that observed in a subset of severely affected autistic children, combined with the loss of age-appropriate social interaction and speech. Clinically, RTT patients often present with core autism-like behavioral deficits, along with RTT specific components that include severe motor abnormalities. In some cases, patients with RTT associated mutations in MeCP2 nevertheless present preserved but affected speech and limited motor abnormalities leading to a diagnosis of ASD that is clinically undifferentiated from idiopathic ASD (Young et al., 2007). Reduced MeCP2 expression is also found in forebrain post-mortem tissue from the majority of idiopathic ASD subjects, suggesting similar epigenetic dysregulation in many cases of idiopathic ASD and RTT (Samaco et al., 2004, Samaco et al., 2005). Such links between MeCP2 and ASD suggest that mice with reduced MeCP2 expression may have construct validity for ASD as well as RTT, and thus models of MeCP2 dysfunction may help understand the distinction between RTT and ASD mechanisms and symptoms. Owing to the lack of well-characterized models of idiopathic ASD yet strong clinical data, changes in auditory and visual evoked phenotypes in a mouse model of RTT may provide additional insight into auditory and visual sensory processing abnormalities found in ASD.

To investigate the role of MeCP2 function on the integrity of sensory processing, this study measured auditory and visual event-related potentials (ERPs) in female mice carrying a single null allele of MeCP2, which replicates the genetic condition leading to RTT (Guy et al., 2001). A number of ERP features common to idiopathic ASD and RTT were observed, including delayed auditory-evoked responses, increased component amplitudes, and gamma-band abnormalities. Each of these differences has been identified in the ASD or RTT clinical population (Castren et al., 2003). These findings suggest that ASD and RTT may share a subset of underlying local circuit abnormalities that contribute to endophenotypic and behavioral abnormalities. Finally, by demonstrating intermediate phenotypic deficits in MeCP2+/− mice, this work helps bridge the divide between clinical and preclinical studies, providing a basis for future pathophysiological investigation and indicates targets for therapeutic development.

Section snippets

Animals and implantation surgery

Female heterozygous Mecp2 null mice (Mecp2tm1.1Bird/J) and littermate controls (n = 9/group) were obtained from The Jackson Laboratory (Bar Harbor ME) and bred in house using males from the background strain (C57/B6J). At 4 months of age, mice underwent stereotaxic implantation of bipolar, twisted, stainless steel electrodes into region CA1 of the hippocampus (AP − 2.2 mm, ML 2.0 mm, DV − 1.9 mm; 100 μm diameter, Plastics One, Roanoke VA). A reference skull screw was implanted over the primary visual

Results

Auditory and visual evoked responses produce a typical set of middle latency positive going (P) and negative going (N) components that are labeled P1–N1–P2 in humans as well as in mice. In response to single stimuli spaced 8 s apart, the ERP responses in both MeCP2+/− and wildtype littermate mice showed this same typical pattern (Fig. 1). Following the P2 there can be another wide positivity (P3) associated with novelty and often an even broader negativity sometimes described as the slow wave.

Discussion

This work demonstrates that MeCP2 heterozygous for a loss of function mutation causes a number of impairments in sensory processing, as measured by auditory and visual evoked-responses. These differences include: increased N1 amplitude, increased latency of auditory P2 component, reduced suppression of induced gamma, and increased suppression of beta-band activity. We identified no differences in ABR, indicating normal initial auditory processing through the brain stem. These results are

Conclusions

These findings are congruent with growing indications that epigenetic mechanisms, such as those associated with MeCP2 and likely in ASD are associated with sensory processing abnormalities. (Schanen, 2006). These results also demonstrate a potential mechanistic link between specific autism-like features of RTT and idiopathic ASD in the auditory processing domain. If this is the case, the MeCP2+/− mouse provides unique access to RTT- and ASD-associated changes in local cortical circuit function.

References (46)

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    The decreased auditory amplitude and prolonged latency of AEP observed in people with RTT (Stauder et al., 2006) were also observed in MecpT158A/Y male mice (Goffin et al., 2012; Goffin et al., 2014). However, contradictory results were reported in MecpNULL/+ female mice (Liao et al., 2012). Overall, parallel studies on the neurophysiological features between people with RTT and mouse models of RTT, and correlations between neurophysiological features and disease severity, remain limited.

  • Sensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review

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    Given these behavioral results, the basic neurophysiologic deficiency reported in RTT is not easily detectable in simple behavioral experiment and seems to manifest itself only in challenging conditions of poor sound perceptibility. No significant alterations in auditory brainstem responses in Mecp2+/− mice (Liao et al., 2012) and in mice lacking Mecp2 in GABAergic neurons (Goffin et al., 2014) were found, perhaps pointing to a cortical origin of the auditory deficits in RTT animal models. Importantly, in sharp contrast to dampened auditory ERP/LFP amplitudes, neuronal firing rate (multi-unit recording) in response to an auditory stimulus (speech sounds presented every 2 s or first clicks/noise burst in a series of transient stimuli) is markedly increased, albeit significantly delayed, in Mecp2-deficient animals thus indicating an enhanced phasic excitability of cortical neurons (Engineer et al., 2015).

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Present Address: Institute of Neuroscience, National Cheng-Chi University, 64, Sec. 2, ZhiNan Rd., Wenshan District, Taipei City 11605, Taiwan.

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