Although Zn2+ is contained in large amounts in the synaptic terminals of hippocampal mossy fibers (MFs), its physiological role in synaptic transmission is poorly understood. By using the newly developed high-sensitivity Zn2+ indicator ZnAF-2, the spatiotemporal dynamics of Zn2+ was monitored in rat hippocampal slices. When high-frequency stimulation was delivered to the MFs, the concentration of extracellular Zn2+ was immediately elevated in the stratum lucidum, followed by a mild increase in the stratum radiatum adjacent to the stratum lucidum, but not in the distal area of stratum radiatum. The Zn2+ increase was insensitive to a non–N-methyl-d-aspartate (NMDA) receptor antagonist but was efficiently attenuated by tetrodotoxin or Ca2+-free medium, suggesting that Zn2+ is released by MF synaptic terminals in an activity-dependent manner, and thereafter diffuses extracellularly into the neighboring stratum radiatum. Electrophysiological analyses revealed that NMDA receptor–mediated synaptic responses in CA3 proximal stratum radiatum were inhibited in the immediate aftermath of MF activation and that this inhibition was no longer observed in the presence of a Zn2+-chelating agent. Thus, Zn2+ serves as a spatiotemporal mediator in imprinting the history of MF activity in contiguous hippocampal networks. We predict herein a novel form of metaplasticity, i.e., an experience-dependent non-Hebbian modulation of synaptic plasticity.

Several methods that enable foreign genes to be transferred directly into germ cells and adult animals have been developed, which have stimulated great interest in manipulating genes in vivo. However, there have been no methods available for introducing genes into fetuses. We report here that a single intravenous injection of expression plasmid: lipopolyamine complexes into pregnant mice resulted in successful gene transfer into the embryos. The transgenes thus introduced were expressed in the fetuses and newborn progeny. This simple and new method of gene transfer into embryos will facilitate rapid analysis of transgene effects in the fetuses and will be useful for studying gene-deficient animal models to gain transgene functions at desired stages of embryogenesis.

BackgroundThree different subsets of circulating human monocytes, CD14brightCD16- (classical), CD14brightCD16+ (intermediate), and CD14dimCD16+ (non-classical) have been recently identified. It has been reported that CD14brightCD16+ monocytes are increased in rheumatoid arthritis (RA). However, the role of each monocyte subset in the pathogenesis of RA is still unclear. The purpose of this study was to investigate the association of CD14brightCD16+ monocytes with RA.MethodsThe study enrolled 35 patients with RA and 14 healthy volunteers. The three subsets of peripheral blood monocytes were analyzed by flow cytometry. Serum cytokines were measured at baseline in patients with RA and in healthy volunteers. CD14brightCD16- monocytes were isolated and cultured in vitro with different cytokines for 14 hours, and CD16 induction was assessed.ResultsThe proportion of CD14brightCD16+ monocytes, and serum interleukin (IL)-6, IL-8, and IL-10 were increased in patients with RA compared to healthy controls. The proportion of CD14brightCD16+ monocytes correlated with the disease activity of RA positively, whereas the proportion of CD14brightCD16- monocytes correlated negatively. When isolated CD14brightCD16- monocytes were stimulated with IL-6, IL-8, and IL-10, the only cytokine that significantly induced CD16 expression on the cells was IL-10.ConclusionsThe proportion of CD16brightCD14+ monocytes was positively correlated with RA disease activity. The expression of CD16 in monocytes was induced by IL-10 but not IL-6, and IL-8 was enhanced in the sera of patients with RA. Our results suggest that CD16brightCD14+ monocytes are involved in the pathogenesis of RA and that IL-10 is a key cytokine that regulates CD16 expression in monocytes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1216-6) contains supplementary material, which is available to authorized users.

Hippocampal CA3 pyramidal cells receive two independent afferents from the enthorinal cortex, i.e. a direct input via the temporoammonic pathway (TA, perforant path) and an indirect input via the mossy fibres (MF) of dentate granule cells. In spite of past suggestions that the TA is assigned an important role in exciting the pyramidal cells, little is known about their physiological properties. By surgically making an incision through the sulcus hippocampi and a small part of the dentate molecular layer, we succeeded in isolating TA‐mediated monosynaptic responses in CA3 stratum lacunosum‐moleculare. The TA‐CA3 synaptic transmission was completely blocked by a combination of d,l‐2‐amino‐5‐phosphonopentanoic acid (AP5) and 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX), NMDA and non‐NMDA receptor antagonists, respectively, and displayed paired‐pulse facilitation and NMDA receptor‐dependent long‐term potentiation, which are all typical of glutamatergic synapses. We next addressed the heterosynaptic interaction between TA‐CA3 and MF‐CA3 synapses. The TA‐CA3 transmission was partially attenuated by single‐pulse MF pre‐stimulation at inter‐pulse intervals of up to 70 ms. However, surprisingly, burst stimulation of the MF alone induced long‐lasting facilitation of TA‐CA3 synaptic efficacy. This non‐Hebbian form of synaptic plasticity was efficiently prevented by local application of AP5 into the MF synapse‐rich area. Therefore, MF‐activated NMDA receptors are responsible for the heterosynaptic modification of TA‐CA3 transmission, and thereby, the history of MF activity may be etched into TA‐CA3 synaptic strength. Our findings predict a novel form of spatiotemporal information processing in the hippocampus, i.e. a use‐dependent intersynaptic memory transfer.

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