Neurobehavioral Phenotype Analysis in Molecular Intervention Models of Mir-137 Expression

Abstract

Small non-coding microRNA (miRNA) coordinate mRNA translation and stability, and their dysregulation is thought to have significant consequences in psychiatric disorders. This hypothesis is clearly supported by strong genome-wide association of the MIR137 containing locus with schizophrenia. In accordance with previous studies, we show that the common risk variant is associated with reduced expression of the mature miRNA in postmortem dorsolateral prefrontal cortex, whereas no difference was observed on a case-control basis in schizophrenia. To try and understand the functional significance of developmental and acute alteration of this molecule in the brain, we used both chemical and transgenic approaches in the zebrafish. While overexpression produced no noticeable phenotype, miR-137 suppression by morpholino antisense and transgene directed miR-sponge expression, produced a significant sensorimotor phenotype in response to touch stimuli. The absence of anatomical or histological pathology in the nervous system of these animals, suggested that the behavioral phenotype was more likely due to a change in synaptic function and neural connectivity. More recently, we observed a significant alteration of neurobehavioural phenotype relevant to schizophrenia in miR-137 overexpressing lentiviral transformed rats. This research suggests that the risk variant is a miR-eQTL responsible for neurodevelopmentally sensitive haploinsufficiency in carriers that manifest as neurocognitive deficits mediated by dysregulation in several pathways involved with schizophrenia and other psychiatric disorders.