Biology subjects

Gunasekaran, S.

Publications and source records attributed to Gunasekaran, S..

2 recordsLinked to original sources

bioRxiv2022

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

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.

neuroscience↗

bioRxiv2021

Novel microRNAs targeting NMDA receptor subunits in animal models of schizophrenia

N-methyl-D-aspartate receptors (NMDAR) are downregulated in schizophrenia possibly through microRNAs (miRNAs) that are differentially expressed in this condition. We screened the miRNAs that are altered in schizophrenia against the targets, Grin2A and Grin2B subunits of NMDAR using bioinformatic tools. Among the predicted miRNAs some interacted with the 3-UTR sequences of Grin2A (miR-296, miR-148b, miR-129-2, miR-137) and Grin2B (miR-296, miR-148b, miR-129-2, miR-223) in dual luciferase assays. This was supported by downregulation of the GluN2B protein in primary hippocampal neurons upon overexpressing Grin2B targeting miRNAs. In two models of schizophrenia-pharmacological MK-801 model and neurodevelopmental methylazoxymethanol acetate (MAM) model which showed cognitive deficits - protein levels of GluN2A and GluN2B were downregulated but their transcript levels were upregulated. MiR-296-3p, miR-148b-5p and miR-137 levels showed upregulation in both models which could have interacted with Grin2A/Grin2B transcripts resulting in translational arrest. In MAM model, reciprocal changes in the expression of the 3p and 5p forms of miR-148b and miR-137 were observed. Expression of neuregulin 1 (NRG1), BDNF and CaMKII, genes implicated in schizophrenia, were also altered in these models. This is the first report of downregulation of GluN2A and GluN2B by miR-296, miR-148b and miR-129-2. Mining miRNAs regulating NMDA receptors might give insights into the pathophysiology of this disorder, providing avenues in therapeutics.

neuroscience↗