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.
Highlights
Aging is often associated with cognitive decline and increased propensity for neurological diseases, leading to a lower quality of life in the elderly (Hedden & Gabrieli, 2004)
We identified 269 miRNAs expressed in the hippocampus, accounting for approximately 30% of all miRNAs identified in mice, in accordance with previous reports showing that the brain is enriched in miRNAs (Noren Hooten et al, 2010; van Spronsen et al, 2013)
We focused our analysis on the relationships between the age-upregulated miRNAs and the expression of genes in the Eph/ephrin pathway as Eph signaling regulates synaptic plasticity and loss of EphB2 has been linked to age-related cognitive dysfunction (Klein, 2008; Cisse et al, 2011)
Summary
Aging is often associated with cognitive decline and increased propensity for neurological diseases, leading to a lower quality of life in the elderly (Hedden & Gabrieli, 2004). The hippocampus is necessary for explicit learning in humans, and hippocampal synapses exhibit robust forms of long-lasting associative synaptic plasticity that appear necessary for certain forms of learning in animals (Burgess et al, 2002). Hippocampal aging is associated with a little change in the hippocampal gross structure or volume; it is associated with biochemical changes in the expression of hundreds of genes involved in neuronal signaling and synaptic plasticity (Blalock et al, 2003). Alzheimer disease (AD), one of the most devastating age-related neurological diseases, involves functional impairment of the hippocampus, and older age is the greatest risk factor for idiopathic AD. Binding of EphB2 to its physiological ligand ephrin initiates signaling pathways critical for neuroplastic processes such as axon guidance, angiogenesis, and long-term potentiation, a form of associative synaptic plasticity observed at hippocampal synapses (Klein, 2008)
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