miR‐204 downregulates EphB2 in aging mouse hippocampal neurons

Abstract

SummaryHippocampal synaptic function and plasticity deteriorate with age, often resulting in learning and memory deficits. As MicroRNAs (miRNAs) are important regulators of neuronal protein expression, we examined whether miRNAs may contribute to this age‐associated decline in hippocampal function. We first compared the small RNA transcriptome of hippocampal tissues from young and old mice. Among 269 hippocampal miRNAs, 80 were differentially expressed (≥ twofold) among the age groups. We focused on 36 miRNAs upregulated in the old mice compared with those in the young mice. The potential targets of these 36 miRNAs included 11 critical Eph/Ephrin synaptic signaling components. The expression levels of several genes in the Eph/Ephrin pathway, including EphB2, were significantly downregulated in the aged hippocampus. EphB2 is a known regulator of synaptic plasticity in hippocampal neurons, in part by regulating the surface expression of the NMDA receptor NR1 subunit. We found that EphB2 is a direct target of miR‐204 among miRNAs that were upregulated with age. The transfection of primary hippocampal neurons with a miR‐204 mimic suppressed both EphB2 mRNA and protein expression and reduced the surface expression of NR1. Transfection of miR‐204 also decreased the total expression of NR1. miR‐204 induces senescence‐like phenotype in fully matured neurons as evidenced by an increase in p16‐positive cells. We suggest that aging is accompanied by the upregulation of miR‐204 in the hippocampus, which downregulates EphB2 and results in reduced surface and total NR1 expression. This mechanism may contribute to age‐associated decline in hippocampal synaptic plasticity and the related cognitive functions.

Thymus aging in mice deficient in either EphB2 or EphB3, two master regulators of thymic epithelium development

“…Many molecules have been involved in the thymus aging, and although in other systems, some Eph have been reported as molecules that reduce the senescence of progenitor cells, 21‐23 their involvement in the aging of the immune system has not been previously investigated. In the intestine, FoxLI, another member of Fox family together with the β‐catenin/TCF‐4 complex, a key component of the Wnt signaling pathway, regulates the expression of EphB2 and EphB3 69 .…”

“…However, their possible participation in the age‐dependent thymic involution has not been studied, although EphB‐deficient thymuses show some characteristics that suggest certain incipient thymic involution, such as hypocellularity, 18 alterations in the TEC phenotype, 19 and occurrence of big epithelial free areas (EFAs) 20 . On the other hand, the involvement of these molecules in aging has been reported in other systems 21‐23 …”

Upregulation of miR‐200a and miR‐204 in MPP+‐treated differentiated PC12 cells as a model of Parkinson’s disease

“…Consistently, miR‐204 was found to be significantly upregulated in HD patients brain and AD patients CSF (Maciotta et al, ; Sinha et al, ). Moreover, miR‐204 was among upregulated miRNAs with age in mouse hippocampal neurons (Mohammed et al, ).…”

Alterations of miRNAs reveal a dysregulated molecular regulatory network in Parkinson’s disease striatum

“…The down-regulated hsa-miR-382 has been shown to influence dopaminergic signaling by interacting with DA D1 receptors [12], a primary target for the PD medication, L-dopa. Previous studies have demonstrated that upregulated hsamiR-204 and hsa-miR-135 mediate synaptic plasticity through the NMDA receptor NR1 subunit [31] and with AMPA receptors [32], respectively. The upregulated miRNA, hsa-miR-223, has been shown to mediate neuroprotection by targeting GluR2 and NR2B receptors [33].…”