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 have been observed in ASD, are thought to reflect deficits in excitatory-inhibitory balance (Gandal et al.; Rojas et al.; Wilson et al.). 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., 2005
; Samaco et al., 2004
). 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 have 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.