Validating γ oscillations and delayed auditory responses as translational biomarkers of autism

Abstract

Background: Difficulty modeling complex behavioral phenotypes in rodents (e.g., language) has hindered pathophysiological investigation and treatment development for autism spectrum disorders. Recent human neuroimaging studies, however, have identified functional biomarkers that can be more directly related to the abnormal neural dynamics of autism spectrum disorders. This study assessed the translational potential of auditory evoked-response endophenotypes of autism in parallel mouse and human studies of autism.

Methods: Whole-cortex magnetoencephalography was recorded in 17 typically developing and 25 autistic children during auditory pure-tone presentation. Superior temporal gyrus activity was analyzed in time and frequency domains. Auditory evoked potentials were recorded in mice prenatally exposed to valproic acid (VPA) and analyzed with analogous methods.

Results: The VPA-exposed mice demonstrated selective behavioral alterations related to autism, including reduced social interactions and ultrasonic vocalizations, increased repetitive self-grooming, and prepulse inhibition deficits. Autistic subjects and VPA-exposed mice showed a similar 10% latency delay in the N1/M100 evoked response and a reduction in γ frequency (30-50 Hz) phase-locking factor. Electrophysiological measures were associated with mouse behavioral deficits. In mice, γ phase-locking factor was correlated with expression of the autism risk gene neuroligin-3 and neural deficits were modulated by the mGluR5-receptor antagonist MPEP.

Conclusions: Results demonstrate a novel preclinical approach toward mechanistic understanding and treatment development for autism.

Conflict of interest statement

Financial Disclosures Drs. Edgar and Roberts report no biomedical financial interests or potential conflicts of interest. Mr. Gandal and Mr. Ehrlichman report no biomedical financial interests or potential conflicts of interest. Ms Mehta reports no biomedical financial interests or potential conflicts of interest.

Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Fig 1

Representative control subjects from clinical (top) and preclinical (bottom) studies. An auditory evoked response is shown above a plot of gamma phase-locking (PLF).

Fig 2

Auditory evoked-responses from clinical and pre-clinical studies in time (A–D) and frequency domains (E–H). A) Grand-average superior temporal gyrus auditory evoked-responses are shown in autism (ASD) and typically developing (TD) groups. B) ASD subjects show a 10% delay in right hemisphere M100 latency. C) Grand-average auditory evoked-responses are shown for mice treated prenatally to valproic acid (VPA) or saline (SAL). D) The VPA group shows a 16% delay in N1 (e.g., M100) latency. E) Transient gamma-band phase-locking (PLF; e.g., intertrial coherence) is significantly reduced in ASD across hemispheres. F) Groups did not differ in evoked (time- and phase-locked) or induced (time-, not phase-locked) gamma power. G) Gamma PLF is reduced in VPA-exposed mice. H) Evoked power was reduced in the VPA group with no difference in induced power. All figures indicate mean ± s.e.m.

Fig 3

Regression analyses between electrophysiological and behavioral measures were performed across clinical and preclinical studies. A) Gamma phase-locking was significantly correlated with M100 latency in clinical subjects (left, R2=0.15, p=0.02, corrected) and with N1 latency in the preclinical study (right, R2=0.25, p<0.02, corrected). The 15–25% shared variance suggests these measures are related but not redundant. B) In mice, gamma phase locking significantly predicated deficits in prepulse inhibition (R2=0.39, p<0.01, corrected), a behavioral measure of sensorimotor integration that is disrupted in autism (64).

Fig 4

Biomarkers are related to the expression of the autism risk gene neuroligin 3 and may be useful therapeutic targets. A) A western blot of neuroligin 3 and β-actin indicates no group differences between SAL and VPA treated adult mice (p=0.1). B) However, NLGN3 protein expression (optical density) significantly predicts gamma phase-locking (R2=0.46, p=0.035, corrected). Note, the VPA-group outlier fits the linear correlation, as it also does in the regression of gamma PLF and PPI (Fig 3B). C) The effect of the mGluR5 antagonist MPEP was assessed on gamma PLF. The plot demonstrates the change in phase-locking (%) after drug administration. A trending interactive effect across SAL and VPA groups suggests that MPEP reduced PLF in the SAL group but boosted gamma synchrony in VPA exposed mice. D) Across both groups, MPEP reduced cortical excitability as measured by N1 amplitude. E) MPEP increased PPI across VPA and SAL groups. Dashed lines indicate that MPEP normalizes PPI deficits in VPA exposed mice. All figures indicate mean ± s.e.m.