Post-mortem analyses of cortical brain tissue in schizophrenia have been shown to display epigenetic changes that reflect early life experience. These affect the regulation of gene expression at the level of transcription, through changes in chromatin structure; and post-transcriptionally through non-coding RNAs, such as microRNA (miRNA). The aim of the current study was to investigate the role of miRNA in the brains’ response to maternal immune activation and adolescent cannabis exposure, alone and in combination, as both have been identified as environmental risk factors for schizophrenia.
Pregnant Wistar rats received an intravenous injection of polyriboinosinic-polyribocytidilic acid (poly I:C) or vehicle on embryonic day 15. Beginning post-natal day (PND) 35, male offspring were treated daily with the synthetic cannabinoid HU210, or vehicle, for 14 days and euthanized on PND 55. Whole genome miRNA microarrays were performed on the left and right entorhinal cortex as this region has been shown to display altered volumes and other anatomical abnormalities in schizophrenia. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited significant differences in miRNA expression, compared to either treatment alone, where only a small effect was observed for each treatment with respect to untreated controls.
This effect was dominated by a large subgroup of miRNA differentially transcribed from a single imprinted locus on chromosome 6q32. In humans, the syntenic locus (14q32) encodes a large proportion of miRNAs found to be differentially expressed in white blood cells from patients with schizophrenia. These miRNA are predicted to target genes highly enriched in pathways repeatedly implicated in the pathophysiology of schizophrenia including Wnt, ErbB and MAP kinase signalling. These results suggest the interaction of both early and late environmental insults, can enhance changes in miRNA expression in the EC, with possible implications for schizophrenia in adulthood.
