miR-146a and miR-200b alter cognition by targeting NMDA receptor subunits

Summary: MicroRNAs fine-tune gene regulation and can be targeted for therapeutic purposes. We investigated the physiological roles of miR-146a and miR-200b that are differentially expressed in neurological disorders such as Alzheimer's disease and schizophrenia, particularly in learning and memory mechanisms. Using bioinformatics tools and luciferase assay, we show interaction of these miRNAs with transcripts of N-methyl-D-aspartate receptor (NMDAR) subunits Grin2A and Grin2B. Overexpression of these miRNAs in primary hippocampal neurons caused downregulation of GluN2B and GluN2A proteins. Stereotactic injections of these miRNAs into rat hippocampus caused cognitive deficits in multiple behavioral tests with decreased protein levels of GluN1, GluN2A, GluN2B, AMPAR subunit GluR1, and Neuregulin 1. In pharmacologically treated rat models [MK-801 treated and methylazoxymethanol acetate (MAM) treated], we found upregulated levels of these miRNAs, implying their involvement in downregulating NMDAR subunits in these models. These results suggest the importance of miR-146a-5p and miR-200b-3p in hippocampus-dependent learning and memory.