Language impairment is a cardinal feature of Autism Spectrum Disorders (ASD) that causes significant disability. Despite this, few viable treatments target communication problems and there remains a poor understanding of how genetic and environmental factors contribute to the development of this core deficit. Current rodent models of autism frequently ignore communicative abnormalities, and thus fail to investigate the full spectrum of core symptoms in ASD. Therefore, the need to develop predictive measures of communication deficits in animal models of ASD which explore underlying mechanisms and potential treatments for language impairment is of paramount importance. The goal of this proposal is to develop and validate electrophysiological and behavioral measures of proto-language functioning in a mouse model of autism. Clinical studies from our collaborators at Children's Hospital of Philadelphia have established a set of electrophysiological biomarkers of impaired receptive language functioning in autistic children using magnetoencephalography. This proposal seeks to translate these clinical findings of impaired auditory-evoked potentials (AEP) to assess proto-language functioning in a mouse model of autism. Proposed studies will investigate AEP changes in mice treated prenatally with the teratogen valproic acid, an established rodent model of autism-like behaviors. Targets will include delayed AEP latencies, altered mismatch negativity, and deficits in gamma oscillations, which have been established as electrophysiological biomarkers of language impairment in clinical studies of autistic subjects.
The second aim i s to assess communicative functioning in these mice with behavioral measures, by assessing newborn and adult ultrasonic vocalizations (USVs). Correlations between behavioral and electrophysiological measures will be assessed to strengthen the validity of these methods. Completion of these studies will further the development of novel methods to assess receptive and expressive communication in mice, thus providing a more complete preclinical paradigm in which to develop new therapeutic treatments for autism.
This project seeks to develop new ways to assess expressive and receptive communication in a mouse model of autism, using EEG techniques to measure electrical brain activity in a way analogous to methods currently used in clinical studies of autistic children. Completion of these studies will help further investigate how genetic and environmental insults can lead to language dysfunction, which is a core behavioral deficit in autism spectrum disorders (ASD). Ultimately, this work will further develop a more complete preclinical paradigm to help uncover underlying disease mechanisms and to develop new treatments for autism.
| Gandal, M J; Anderson, R L; Billingslea, E N et al. (2012) Mice with reduced NMDA receptor expression: more consistent with autism than schizophrenia? Genes Brain Behav 11:740-50 |
