International Meeting for Autism Research: Translational research on interests and reward in autism: identifying novel treatment targets

Translational research on interests and reward in autism: identifying novel treatment targets

Friday, May 13, 2011: 4:30 PM
Douglas Pavilion A (Manchester Grand Hyatt)
3:45 PM
J. W. Bodfish1, J. J. Nadler2 and S. S. Moy3, (1)University of North Carolina - Chapel Hill, Chapel Hill, NC, United States, (2)University of North Carolina at Chapel Hill, Chapel Hill, NC, (3)Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC
Background: Unusual and intense interests, preoccupations and attachments comprise a unique subtype of repetitive behavior, occur commonly in ASD, and can be associated with functional impairment.  We developed a method for quantifying the presence of this phenotypic feature using an exploration paradigm and found that children with ASD demonstrate atypical exploration in general, and explore social stimuli less when nonsocial stimuli associated with unusual interests and preoccupations are present.  The biasing effect of idiosyncratic types of nonsocial stimuli suggests that social and nonsocial sources of information may differ in reward value for persons with ASD.  

Objectives: To develop a preclinical model of interest / reward deficits analogous to those seen in ASD that could be used to identify novel molecular treatment targets and ultimately screen for novel compounds in a high-throughput manner. 

Methods: Our translational studies have proceeded in four stages:  (1) development of a reliable and valid mouse analog of our exploration paradigm for quantifying restricted interests; (2) identification of specific inbred strains of mice that show features of atypical social and repetitive behaviors AND show restricted interests in a social vs. nonsocial stimuli exploration test; (3) examination of candidate inbred strains using high-density genotype data to identify discrete regions of the genome that could be contributing to phenotypic differences associated with atypical exploratory behavior; and (4) cross reference candidate genetic regions with existing data on genetic factors associated with (a) ASD, and (b) atypical motivational behaviors such as addiction.

Results: 6 inbred strains have been tested on a variant of the hole board exploration paradigm using a set of procedural modifications that allow us to examine exploration of social vs. nonsocial stimuli.  Repeated testing confirms stable patterns of strain-specific findings on these parameters of exploration. Among these strains, only C58/J mice show (a) atypical social behavior, (b) increased stereotyped behaviors, and (c) exploratory deficits characterized by increased exploration of nonsocial stimuli relative to social stimuli.  Using available high-density genotype data, we identified genomic regions that are identical-by-descent between C58/J and the two most genetically similar strains in our sample (C57BL/6J and C57L/J) that did not show exploratory deficits.  These regions of the genome are unlikely to contribute to differences in exploratory behavioral phenotype observed in these three strains.  This analysis allows us to exclude over two thirds of the mouse genome from contributing to the behavioral differences observed between these three strains of mice.  One genomic region where the C58/J differs contains several GABA receptor genes that could contribute to the observed differences in exploratory behaviors.

Conclusions: GABA pathways are part of the brain’s “motive circuit” and GABA receptor genes have been associated with autism and with addiction-related disorders.  Thus, GABAergic compounds may represent viable targets for drug development in preclinical models like C58/J that are characterized by social deficits, repetitive behaviors, and prominent restricted nonsocial interests.


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