ABSTRACT
Ischemic stroke is one of the leading causes of death and disability worldwide. Although miR-149-5p downregulation is observed in rats after ischemia/reperfusion (I/R) injury, its function and role in ischemic stroke remain unclear. This study aimed to investigate the roles of miR-149-5p in I/R injury. The results showed that miR-149-5p was significantly downregulated in brain tissues of rats subjected to middle cerebral artery occlusion (MCAO) and primary cortical neurons subject to oxygen and glucose deprivation (OGD). MiR-149-5p overexpression effectively reduced MCAO/R-induced infarct volume, neurological score, and brain water content as well as OGD/R-induced cortical neurons apoptosis and OGD/R-induced expression of TNF-α, IL-4, IL-6, IL-1ß, and COX-2. Moreover, Notch2 was identified as a target of miR-149-5p and Notch2 overexpression significantly attenuated the inhibitory effects of miR-149-5p mimics on inflammation and apoptosis. Taken together, our study revealed that miR-149-5p overexpression protects the rat brain against I/R injury by regulating Notch2-mediated inflammation and apoptosis pathway.
Subject(s)
Brain Ischemia , Ischemic Stroke , MicroRNAs/metabolism , Reperfusion Injury , Animals , Apoptosis , Brain Ischemia/genetics , Brain Ischemia/metabolism , Glucose/metabolism , Infarction, Middle Cerebral Artery/genetics , Infarction, Middle Cerebral Artery/metabolism , Inflammation , Ischemic Stroke/metabolism , MicroRNAs/genetics , Oxygen , Rats , Receptor, Notch2/genetics , Reperfusion , Reperfusion Injury/genetics , Reperfusion Injury/metabolism , Reperfusion Injury/prevention & controlABSTRACT
Background: The CTNND2 gene which encodes a δ-catenin protein (CTNND2) is associated with multiple severe neurological disorders. However, the specific role of CTNND2 in spatial cognition and related mechanisms remains obscure. Methods: In this study, we generated a new line of Ctnnd2-Knock out (KO) mice with its exon2 deleted, and then characterized their behavioral phenotypes and explore the Biological mechanism. Results: Ctnnd2-KO mice were with typical autism-like behaviors as evidenced by reduced social interaction in three-chamber sociability test, more frequent stereotypic behaviors (self-grooming), and deficits in spatial learning and memory tested by the Morris water maze. Furthermore, the expression of Rictor protein, a core component of the mTORC2 complex, was significantly decreased in the hippocampus of mutant mice. ShRNA-induced knockdown of Rictor protein in the hippocampus of both Ctnnd2-KO mice and wild-type mice exacerbated spatial learning and memory deficits but did not affect their autism-like behaviors. Mechanistically, the hippocampal CA1 neurons of Ctnnd2-KO mice showed decreased actin polymerization, postsynaptic spine density. Down-regulation of Rictor resulted in altered expression of post-synaptic proteins such as GluR1 and ELKS, but not presynaptic protein Synapsin1, implying abnormal synaptic changes in KO mice. Conclusion: The CTNND2 gene is involved in spatial learning and memory via Rictor-mediated actin polymerization and synaptic plasticity. Our study provides a novel insight into the role and mechanisms of the Ctnnd2 gene in cognition at the molecular and synaptic levels.
