Validating γ oscillations and delayed auditory responses as translational biomarkers of autism.
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.
Department of Psychiatry, University of Pennsylvania, Philadelphia, 19104, USA.
Michael J
MJ
Gandal
J Christopher
JC
Edgar
Richard S
RS
Ehrlichman
Mili
M
Mehta
Timothy P L
TP
Roberts
Steven J
SJ
Siegel
D000818:Animals; D000831:Animals, Newborn; D001307:Auditory Perception / Q000502:physiology*; D001321:Autistic Disorder / Q000503:physiopathology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers; D058256:Brain Waves / Q000502:physiology*; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis; D002540:Cerebral Cortex / Q000503:physiopathology; D002648:Child; D004195:Disease Models, Animal; D058068:Endophenotypes; D005072:Evoked Potentials, Auditory / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D015225:Magnetoencephalography / Q000379:methods; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D013702:Temporal Lobe / Q000503:physiopathology; D014635:Valproic Acid / Q000009:adverse effects / Q000037:antagonists & inhibitors
D015415:Biomarkers; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011725:Pyridines; C098004:neuroligin 3; D014635:Valproic Acid; C121465:6-methyl-2-(phenylethynyl)pyridine