miR - 218 - 2 regulates cognitive functions in the hippocampus through complement component 3–dependent modulation of synaptic vesicle release

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.

miR-218: A Stress-Responsive Epigenetic Modifier

“…The Netrin-1/DCC signaling pathway, along with the others, impacts neuronal development and synaptic plasticity [ 31 ]. MiR-218 is expressed throughout the brain, notably in the hippocampus and PFC [ 30 ]. It is expressed at various levels through life stages as seen by adolescent and adult animal models, which again implicates its role in development [ 89 ].…”

“…In this case, the regulation primarily happens through AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-mediated excitatory transmission. Studies have shown that miR-218 abundance is regulated during hippocampal development and by chronic silencing or activation of neuronal networks [ 29 , 30 , 101 ]. Overexpression and knockdown of miR-218 demonstrated that miR-218 targets the mRNA encoding the GluA2 subunit of AMPA receptors and modulates its expression.…”

“…One such stress-responsive miRNA is miR-218 which has recently emerged with functional roles in modulating the signaling pathways and related gene expression in animal stress models [ 28 ]. Increasing focus on miR-218 has been associated with various brain functions, including synaptic plasticity, cell survival, and behavior [ 29 , 30 ]. Our group and other investigators have shown that this miRNA is involved in stress and susceptibility to developing depression and can be used as a biomarker for diagnosing stress-related disorders [ 31 , 32 , 33 ].…”

Dysregulated miRNAs as Biomarkers and Therapeutical Targets in Neurodegenerative Diseases

“…In addition to PD, AD, and ALS ( Table 1 , Table 2 and Table 3 , Figure 1 ), miR-218, has been associated with neuropsychiatric disorders and other NDs [ 135 , 249 , 267 , 268 ]. In AD it is considered a potential peripheral biomarker [ 95 ] and was shown to regulate learning and memory in a mice AD model [ 94 ] and to affect the homeostasis between phosphorylated and dephosphorylated tau proteins [ 93 ] ( Table 1 , Figure 2 ). In PD models, miR-218 plays a role in modulating the NF-κB inflammatory signaling pathway, by influencing the activity of three importins, KPNB1, KPNA3, and KPNA4 [ 107 ], and interacts with the PD related gene PRKN [ 269 ], leading to mitochondrial dysfunction through the autophagic pathway [ 188 ] ( Table 2 , Figure 2 ).…”

Dysregulated miRNAs network in the critical COVID-19: An important clue for uncontrolled immunothrombosis/thromboinflammation

“…Different complement components and regulators are among the target molecules of miRNAs. For instance, miR-145, miR-150, miR-218–2, and miR-92-d negatively regulate the C3 and miR-328 induces its deposition [213] , [214] , [215] , [216] . The miR-494-3p and miR-574 also target the C7 [217] ( Fig.…”