Based on a wide-ranging profile of autism-relevant behaviors, the BTBR T+tf/J (BTBR) mouse is the most widely accepted mouse model of idiopathic autism. Recent work from this lab indicated a widespread disturbance in the molecular composition of the extracellular matrix in the subventricular zone of the lateral ventricles (LV-SVZ) in BTBR, compared to C57BL/6J (control) mice. Deep reductions in heparan sulfates (HS), linear polysaccharides that interact with a range of growth and guidance factors in the LV-SVZ, and in laminin, suggest a potential mechanism/location for the disturbed hodology of the autistic brain. Evaluation of this hypothesis involved 4 pairs of autism-diagnosed individuals (ADI) with age- and sex- (all male) matched typically developing (TD) controls. In the TD controls, HS levels declined sharply with increasing age, consonant with a particular function for HS in the developing brain. Overall, ADI had significantly less HS than TD, but this difference was most profound in the younger samples, disappearing in the age 60+ pair. Laminin levels were consistent for TD, but extremely variable for ADI. We now have a total of 18 ADI-TD age- and sex-matched pairs, and are examining gene expression and DNA methylation profiles in the LV-SVZ of individuals diagnosed with autism. We expect that changes localized to the LV-SVZ will provide greater specificity concerning epigenetic factors involved in the brain dysfunctions associated with the disorder.
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