title: miR-204 downregulates EphB2 in aging mouse hippocampal neurons.
abstract: Hippocampal 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.
authors.affiliation: Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 711-873, Korea.|Department of New Biology, DGIST, Daegu, 711-873, Korea.|Department of Life Sciences, POSTECH, Pohang, 790-784, Korea.
authors.forename: Chand Parvez Danka
authors.initials: CP
authors.lastname: Mohammed
authors.affiliation: Macrogen Inc., Seoul, 153-781, Korea.
authors.forename: Hwanseok
authors.initials: H
authors.lastname: Rhee
authors.affiliation: Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 711-873, Korea.
authors.forename: Bong-Kwan
authors.initials: BK
authors.lastname: Phee
authors.affiliation: Department of New Biology, DGIST, Daegu, 711-873, Korea.
authors.forename: Kunhyung
authors.initials: K
authors.lastname: Kim
authors.affiliation: Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 711-873, Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of New Biology, DGIST, Daegu, 711-873, Korea.
authors.forename: Hyehyeon
authors.initials: H
authors.lastname: Lee
authors.affiliation: Macrogen Inc., Seoul, 153-781, Korea.
authors.forename: Jung Hoon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Macrogen Inc., Seoul, 153-781, Korea.
authors.forename: Jung Hee
authors.initials: JH
authors.lastname: Jung
authors.affiliation: Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 711-873, Korea.
authors.forename: Jeong Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Ochang, 363-883, Korea.
authors.forename: Hyoung-Chin
authors.initials: HC
authors.lastname: Kim
authors.affiliation: Department of Life Sciences, POSTECH, Pohang, 790-784, Korea.
authors.forename: Sang Ki
authors.initials: SK
authors.lastname: Park
authors.affiliation: Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 711-873, Korea.|Department of New Biology, DGIST, Daegu, 711-873, Korea.
authors.forename: Hong Gil
authors.initials: HG
authors.lastname: Nam
authors.affiliation: Department of New Biology, DGIST, Daegu, 711-873, Korea.
authors.forename: Keetae
authors.initials: K
authors.lastname: Kim
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015536:Down-Regulation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D036183:Receptor, EphB2 / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C121673:Gprin1 protein, mouse; C574692:MIRN204 microRNA, mouse; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C586311:Ephb2 protein, mouse; D036183:Receptor, EphB2
keywords: EphB2; NMDA receptor; aging; hippocampus; miRNA204