Dysregulation of miRNAs Levels in Glycogen Synthase Kinase-3β Overexpressing Mice and the Role of miR-221-5p in Synaptic Function

Glycogen synthase kinase-3 beta (GSK-3 beta) is a highly expressed kinase in the brain, where it has an important role in synaptic plasticity. Aberrant activity of GSK-3 beta leads to synaptic dysfunction which results in the development of several neuropsychiatric and neurological diseases. Notably, overexpression of constitutively active form of GSK-3 beta (GSK-3 beta[S9A]) in mice recapitulates the cognitive and structural defects characteristic for neurological and psychiatric disorders. However, the mechanisms by which GSK-3 beta regulates synaptic functions are not clearly known. Here, we investigate the effects of GSK-3 beta overactivity on neuronal miRNA expression in the mouse hippocampus. We found that GSK-3 beta overactivity downregulates miRNA network with a potent effect on miR-221-5p (miR-221*). Next, characterization of miR-221* function in primary hippocampal cell culture transfected by miR-221* inhibitor, showed no structural changes in dendritic spine shape and density. Using electrophysiological methods, we found that downregulation of miR-221* increases excitatory synaptic transmission in hippocampal neurons, probably via postsynaptic mechanisms. Thus, our data reveal potential mechanism by which GSK-3 beta and miRNAs might regulate synaptic function and therefore also synaptic plasticity. (C) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.