MicroRNAs (miRNAs) are prominently expressed in the CNS and can be involved in different stages of neural development and differentiation. They have also been implicated in synapse plasticity based on the demonstrated FMR1-miRNA and MeCP2-miRNA interplays. Moreover, there is evidence for miRNAs involvement in the pathogenesis of some neurodevelopmental disorders such as schizophrenia. We used Illumina human miRNA arrays (representing 735 miRNAs) to evaluate possible miRNA dysregulation in autism spectrum disorder (ASD). miRNA expression profiles in lymphoblastoid cultures from 10 male Caucasian ASD cases were compared to sex and age matched non-ASD sibling controls. We found seven interesting miRNAs (p value <0.008) with aberrant expression profiles including miR-132. MeCP2 is the experimentally validated target of miR-132. Considering MeCP2 mutations cause Rett syndrome of which some cases have autism, our findings seem functionally relevant. We also queried for global gene expression variation using the Illumina gene expression array (containing 48,000 probes) and found 44 genes (p value <0.001) differentially expressed in affected individuals compared to their unaffected sibs. Interestingly, using Ingenuity pathway analysis only three main pathways were identified amongst these 44 genes, which contained over 80% of the pathway eligible genes. This suggests that the majority of the genes identified as being differentially regulated are interacting with each other. We are currently genotyping these individuals to test for associated haplotypes. In a second approach we also tested for dysregulation of Neuregulin 1 (NRG1)-related pathways in autism. NRG1 has been associated with schizophrenia, a condition that is observed in higher frequencies in families affected with ASD. Cell cultures were prepared from the same 10 individuals selected for the miRNA study. They were treated with NRG1 and subsequently miRNA and global gene expression profiles of the treated cells were compared to that of the untreated cells. The NRG1 treatment of lymphoblastoid cells from affected and unaffected individuals did not reveal significant differences, but some miRNA and gene pathways regulated by NRG1 were found.

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