Convergence of circuit dysfunction in ASD: a common bridge between diverse genetic and environmental risk factors and common clinical electrophysiology.

Russell G Port,Gregory C Carlson,Michael J Gandal,Steven J Siegel,Timothy P L Roberts

doi:10.3389/fncel.2014.00414

Abstract

Most recent estimates indicate that 1 in 68 children are affected by an autism spectrum disorder (ASD). Though decades of research have uncovered much about these disorders, the pathological mechanism remains unknown. Hampering efforts is the seeming inability to integrate findings over the micro to macro scales of study, from changes in molecular, synaptic and cellular function to large-scale brain dysfunction impacting sensory, communicative, motor and cognitive activity. In this review, we describe how studies focusing on neuronal circuit function provide unique context for identifying common neurobiological disease mechanisms of ASD. We discuss how recent EEG and MEG studies in subjects with ASD have repeatedly shown alterations in ensemble population recordings (both in simple evoked related potential latencies and specific frequency subcomponents). Because these disease-associated electrophysiological abnormalities have been recapitulated in rodent models, studying circuit differences in these models may provide access to abnormal circuit function found in ASD. We then identify emerging in vivo and ex vivo techniques, focusing on how these assays can characterize circuit level dysfunction and determine if these abnormalities underlie abnormal clinical electrophysiology. Such circuit level study in animal models may help us understand how diverse genetic and environmental risks can produce a common set of EEG, MEG and anatomical abnormalities found in ASD.

Highlights

We identify emerging in vivo and ex vivo techniques, focusing on how these assays can characterize circuit level dysfunction and determine if these abnormalities underlie abnormal clinical electrophysiology
To do so we first summarize the current literature of observed alterations to neural circuits in autism spectrum disorder (ASD), with a focus on mechanisms that may underlie the E/MEG phenotypes found in human subjects. We propose that it is at the mesoscopic circuit level, local circuit function that leads to high frequency activity, where many diverse alterations must integrate to produce the symptomatology of ASD
First-degree relatives of patients with ASD often exhibit a broad autism phenotype (Losh et al, 2008), and as such may reflect this behavioral predisposition. This leads to hypothesis that electrophysiological makers such as M100 delay and gammaband dysfunction may signal a risk for ASD or schizophrenia rather than be a sign of the disease, more clinical work is needed to better understand the role of high-frequency changes in activity associated with ASD

Summary

Introduction

Such circuit level study in animal models may help us understand how diverse genetic and environmental risks can produce a common set of EEG, MEG and anatomical abnormalities found in ASD. EEG AND MEG STUDIES PRESENT COMMON CLINICAL NEUROPHYSIOLOGICAL DIFFERENCES IN ASD In contrast to the divergent assortment of complex combinatorial risks found for ASD, clinical electrophysiology has identified specific resting, event related potential, and spectral changes that suggest common neural circuit function abnormalities (Figure 1).

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