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

Abstract

MicroRNAs (miRNAs) play pivotal roles in fine-tuning gene regulation. Understanding the mechanism of action of such miRNAs might help in manipulating the respective pathways thus providing therapeutic options. We have investigated the physiological roles of two miRNAs, miR-146a and miR-200b, that are differentially expressed in neurological disorders such as Alzheimers disease andschizophrenia.We specifically studied their involvement in learning and memory mechanisms. We show through bioinformatics prediction tools that these miRNAs can interact with transcripts of the N-methyl-D-aspartate receptor (NMDAR) subunits Grin2A and Grin2B. This was further supported by showing interaction of the miRNAs to the 3UTR sequences of Grin2A and Grin2B through luciferase assay. Overexpression of these miRNAs in primary hippocampal neurons caused downregulation of GluN2B and GluN2A protein levels. Stereotactic injections of these miRNAs into rat hippocampus caused cognitive deficits in multiple behavioural tests along with decreased protein levels of the NMDAR subunits, GluN1, GluN2A and GluN2B, AMPAR subunit GluR1 and Neuregulin 1 (NRG1). During downregulation of NMDAR subunits by other physiological stimuli as in pharmacologically treated rat models [MK-801 treated and methylazoxymethanol acetate (MAM) treated], we found upregulated levels of miR-146a-5p and miR-200b-3p implying their involvement in downregulating NMDAR subunits. These results suggest the importance of miR-146a-5p and miR-200b-3p in mediating gene regulation in the hippocampus and their involvement in hippocampus dependent learning and memory.