Banach Ewa, Szczepankiewicz Aleksandra, Kaczmarek Leszek, Jaworski Tomasz, Urban-Ciećko Joanna
Laboratory of Electrophysiology, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland; Laboratory of Animal Models, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland; Laboratory of Neurobiology, BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland.
Molecular and Cell Biology Unit, Poznan University of Medical Sciences, 60-572 Poznan, Poland.
Neuroscience. 2022 May 10;490:287-295. doi: 10.1016/j.neuroscience.2022.03.024. Epub 2022 Mar 21.
Glycogen synthase kinase-3β (GSK-3β) is a highly expressed kinase in the brain, where it has an important role in synaptic plasticity. Aberrant activity of GSK-3β leads to synaptic dysfunction which results in the development of several neuropsychiatric and neurological diseases. Notably, overexpression of constitutively active form of GSK-3β (GSK-3β[S9A]) in mice recapitulates the cognitive and structural defects characteristic for neurological and psychiatric disorders. However, the mechanisms by which GSK-3β regulates synaptic functions are not clearly known. Here, we investigate the effects of GSK-3β overactivity on neuronal miRNA expression in the mouse hippocampus. We found that GSK-3β 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-3β and miRNAs might regulate synaptic function and therefore also synaptic plasticity.
糖原合酶激酶-3β（GSK-3β）是大脑中高表达的一种激酶，在突触可塑性中发挥重要作用。GSK-3β的异常活性会导致突触功能障碍，进而引发多种神经精神疾病和神经疾病。值得注意的是，在小鼠中过表达组成型活性形式的GSK-3β（GSK-3β[S9A]）会重现神经和精神疾病特有的认知和结构缺陷。然而，GSK-3β调节突触功能的机制尚不清楚。在此，我们研究了GSK-3β活性过高对小鼠海马体中神经元微小RNA（miRNA）表达的影响。我们发现，GSK-3β活性过高会下调miRNA网络，对miR-221-5p（miR-221*）有显著影响。接下来，在经miR-221抑制剂转染的原代海马细胞培养物中对miR-221功能进行表征，结果显示树突棘形状和密度没有结构变化。使用电生理方法，我们发现miR-221*的下调可能通过突触后机制增加海马神经元中的兴奋性突触传递。因此，我们的数据揭示了GSK-3β和miRNA可能调节突触功能以及突触可塑性的潜在机制。
