On Mar.29, 2021, Jun Yao's Group published 'miR-218-2 regulates cognitive functions in the hippocampus through complement component 3-dependent modulation of synaptic vesicle release' in PNAS.

Significance

Several neurodegenerative and neuropsychiatric disorders with cognitive symptoms show an abnormal expression of microRNA-218 (miR-218). In this study, we demonstrated that miR-218 regulated presynaptic functions and learning related behaviors through targeting the 3′-untranslated region (UTR) of the mRNA of complement component 3 (C3), a central component of the immune system. This finding may represent a common mechanism for the defective cognition of multiple neuronal disorders with miR-218 deficits and provide a strategy for the development of new therapy.

Abstract

microRNA-218 (miR-218) has been linked to several cognition related neurodegenerative and neuropsychiatric disorders. However, whether miR-218 plays a direct role in cognitive functions remains unknown. Here, using the miR-218 knockout (KO) mouse model and the sponge/overexpression approaches, we showed that miR-218-2 but not miR-218-1 could bidirectionally regulate the contextual and spatial memory in the mice. Furthermore, miR-218-2 deficiency induced deficits in the morphology and presynaptic neurotransmitter release in the hippocampus to impair the long term potentiation. Combining the RNA sequencing analysis and luciferase reporter assay, we identified complement component 3 (C3) as a main target gene of miR-218 in the hippocampus to regulate the presynaptic functions. Finally, we showed that restoring the C3 activity in the miR-218-2 KO mice could rescue the synaptic and learning deficits. Therefore, miR-218-2 played an important role in the cognitive functions of mice through C3, which can be a mechanism for the defective cognition of miR-218 related neuronal disorders.