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MicroRNA Networks in Neuronal Development and Plasticity

Final Report Summary - NEURO-MIR-NETWORKS (MicroRNA Networks in Neuronal Development and Plasticity)

The overall goal of the Neuro-miR-Networks project was to investigate the epigenetic role of a RNA regulatory network as it relates to the pathogenesis of intellectual disability (ID) and autism spectrum disorder (ASD). These are severe neurodevelopmental disorders, marked by impairments in reciprocal social interaction, delays in early language and communication, and the presence of restrictive, repetitive and stereotyped behaviors. Our proposed study is compelled by the hypothesis that altered microRNA (miRNA) pathway leads to synapse dysfunction, underlying the cognitive deficits associated with behavioural and neuropathological abnormalities associated with this disorder. MicroRNAs (miRNAs) are small non-coding RNAs that confer robustness to complex gene networks through post-transcriptional regulation of gene expression. Recent data generated in the past by us and others, demonstrated that a) miRNAs are abundantly expressed in the vertebrate nervous system, where they contribute to the specification of neuronal cell identity, and b) miRNA expression is modulated by synaptic activity, which is considered essential for learning and memory formation. The overall goal of our research was that identifying miRNA-mediated pathways involved in synapse development and plasticity may provide opportunities to develop intervention strategies for abnormalities associated with mental illness. Our findings suggest that a brain-enriched microRNA that is associated with intellectual disability and Autism, namely miR-137, is a key factor in the control of synaptic efficacy and mGluR- dependent synaptic plasticity, supporting the notion that glutamatergic dysfunction may contribute to the pathogenesis of miR-137-linked cognitive impairments. We further provided several lines of evidence for a key role for miR-137 in controlling synaptic efficacy and plasticity. Our study also suggests that endogenous miR-137 functions as a synaptic break during development and regulates excitatory synaptic strength through direct modulation of AMPA receptor subunit, GluA1, levels. In this study we link genetic deficits in MIR137 to glutamatergic dysfunction, which may contribute to our understanding of the pathogenesis of miR-137-linked cognitive impairments. The results summarised here have been recently resubmitted after a detailed revision work to the journal Cell Reports.

In a second line of study we examined the role of microRNAs in ASD using an animal models of this disorder. Our studies suggest that a valproic acid (VPA) rat model of ASD exhibits an enlargement of the amygdala as compared to controls rats, similar to that observed in adolescent ASD individuals. Since recent research suggests that altered neuronal development and morphology, as seen in ASD, may result from a common post-transcriptional process that is under tight regulation by microRNAs (miRs), we examined genome-wide transcriptomics expression in the amygdala of rats prenatally exposed to VPA, and detected elevated miR-181c and miR-30d expression levels as well as dysregulated expression of their cognate mRNA targets encoding proteins involved in neuronal system development. Furthermore, selective suppression of miR-181c function attenuates neurite outgrowth and branching, and results in reduced synaptic density in primary amygdalar neurons in vitro. Collectively, these results implicate the small non-coding miR-181c in neuronal morphology, and provide a framework of understanding how dysregulation of a neurodevelopmentally relevant miR in the amygdala may contribute to the pathophysiology of ASD. The results summarized here have been recently resubmitted after a detailed revision work to the journal Neurobiology of Disease.