Cellular origins of auditory event-related potential deficits in Rett syndrome.

Dysfunction in sensory information processing is a hallmark of many neurological disorders, including autism spectrum disorders, schizophrenia and Rett syndrome (RTT). Using mouse models of RTT, a monogenic disorder caused by mutations in MECP2, we found that the large-scale loss of MeCP2 from forebrain GABAergic interneurons led to deficits in auditory event-related potentials and seizure manifestation, whereas the restoration of MeCP2 in specific classes of interneurons ameliorated these deficits.

Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy. The biological function of CDKL5 and its role in the etiology of these disorders, however, remain unclear. Here we report the development of a unique knockout mouse model of CDKL5-related disorders and demonstrate that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory. Neurophysiological recordings reveal alterations in event-related potentials (ERPs) similar to those observed in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKT-mammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 regulates signal transduction pathways and mediates autistic-like phenotypes and together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders.

NMDA antagonist MK801 recreates auditory electrophysiology disruption present in autism and other neurodevelopmental disorders.

Autism is a highly disabling neurodevelopmental disorder characterized by social deficits, language impairment, and repetitive behaviors. There are few effective biological treatments for this disorder, partly due to the lack of translational biomarkers. However, recent data suggest that autism has reliable electrophysiological endophenotypes, along with evidence that some deficits may be caused by NMDA receptor (NMDAR) dysfunction. Similarly, the NMDAR antagonist MK801 has been used in behavioral animal models of autism. Since MK801 has also been used as a model of schizophrenia, this paper examines the independent and overlapping ways in which MK801 recreates the electrophysiogical changes present in both diseases. Mouse EEG was recorded in response to auditory stimuli after either vehicle or MK801 and the dose-response relationship for each measure was determined. ERP component amplitude and latency analysis was performed along with time-frequency analysis of gamma frequency inter-trial coherence and evoked power. Evoked gamma power and ITC were decreased by MK801 at the highest dose. P1, N1 latency and gamma baseline power were increased in dose dependent fashion following MK801. There were no amplitude changes in P1 or N1. MK801 caused alterations in evoked gamma activity, gamma ITC, gamma baseline power, P1 and N1 latency similar to findings in autism. These data provide evidence indicating that NMDAR dysfunction may contribute to deficits specific to autism and some that overlap with other disorders such as schizophrenia. Such observations could be important for developing novel therapeutics, as electrophysiological endophenotypes associate with functional measures and may provide early biomarkers for efficacy in clinical trials.

NMDA antagonists recreate signal-to-noise ratio and timing perturbations present in schizophrenia.

RATIONALE: There is increasing evidence that functional deficits in schizophrenia may be driven by a reduction in the signal-to-noise ratio (SNR) and consistent timing of neural signals. This study examined the extent to which exposure to the NMDA receptor antagonists ketamine and MK801, frequently used pharmacological models of schizophrenia, recreate deficits in electrophysiological markers of disturbed brain circuits that are thought to underlie the illness. Furthermore, this study characterizes the specificity of these differences across the frequency spectrum so as to help identify the nature of selective circuit abnormalities that mediate each oscillatory response as relevant to schizophrenia. DESIGN: Mouse EEG was recorded during exposure to repeated auditory stimuli after injection of either vehicle or drug. The dose-response relationship for each electrophysiological measure was determined for ketamine and MK-801. Time-frequency analyses were performed to assess baseline, total, and evoked power and intertrial coherence (ITC) at low (5-10 Hz) and high (35-80 Hz)-frequencies. RESULTS: High frequency evoked and total power was decreased by MK-801 and ketamine in a dose-dependent fashion. High frequency baseline power was increased by MK-801 and ketamine in a dose-dependent fashion. Similar to evoked power, high frequency inter-trial coherence was dose-dependently decreased by both drugs. Low frequency ITC was only decreased by ketamine. CONCLUSIONS: Both ketamine and MK-801 cause alterations in high-frequency baseline (noise), total (signal), and evoked (signal) power resulting in a loss of high frequency SNR that is thought to primarily reflect local circuit activity. These changes indicate an inappropriate increase in baseline activity, which can also be interpreted as non-task related activity. Ketamine induced a loss of intertrial coherence at low frequencies, indicating a loss of consistency in low-frequency circuit mechanisms. As a proportion of baseline power, both drugs had a relative shift from low to high frequencies, reflecting a change in the balance of brain activity from coordination of global regions to a pattern of discoordinated, autonomous local activity. These changes are consistent with a pattern of fragmented regional brain activity seen in schizophrenia.

Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses.

Mutations in the MECP2 gene cause the autism spectrum disorder Rett syndrome (RTT). One of the most common MeCP2 mutations associated with RTT occurs at threonine 158, converting it to methionine (T158M) or alanine (T158A). To understand the role of T158 mutations in the pathogenesis of RTT, we generated knockin mice that recapitulate the MeCP2 T158A mutation. We found a causal role for T158A mutation in the development of RTT-like phenotypes, including developmental regression, motor dysfunction, and learning and memory deficits. These phenotypes resemble those present in Mecp2 null mice and manifest through a reduction in MeCP2 binding to methylated DNA and a decrease in MeCP2 protein stability. The age-dependent development of event-related neuronal responses was disrupted by MeCP2 mutation, suggesting that impaired neuronal circuitry underlies the pathogenesis of RTT and that assessment of event-related potentials (ERPs) may serve as a biomarker for RTT and treatment evaluation.