Presynaptic ionotropic glutamate receptors are emerging as key players in the regulation of synaptic transmission. Here we identify GluR7, a kainate receptor (KAR) subunit with no known function in the brain, as an essential subunit of presynaptic autoreceptors that facilitate hippocampal mossy fiber synaptic transmission. GluR7 ؊/؊ mice display markedly reduced short-and long-term synaptic potentiation. Our data suggest that presynaptic KARs are GluR6/ GluR7 heteromers that coassemble and are localized within synapses. We show that recombinant GluR6/GluR7 KARs exhibit low sensitivity to glutamate, and we provide evidence that presynaptic KARs at mossy fiber synapses are likely activated by high concentrations of glutamate. Overall, from our data, we propose a model whereby presynaptic KARs are localized in the presynaptic active zone close to release sites, display low affinity for glutamate, are likely Ca 2؉ -permeable, are activated by single release events, and operate within a short time window to facilitate the subsequent release of glutamate.kainate receptors ͉ presynaptic glutamate receptors ͉ short-term plasticity ͉ synaptic plasticity

The antioxidant potentials of a total ethanolic extract of Hypericum perforatum (TE) and fractions were evaluated and correlated with their phenolic contents. The extracts were fully characterised by HPLC-DAD-MS-MS. Kaempferol 3-rutinoside and rutinacetyl were identified for the first time in TE extracts. The free radical-scavenging properties of TE (EC 50 ¼ 21 lg dwb/ml) and fractions were studied using DPPH. Fractions containing flavonoids and/or caffeoylquinic acids were found to be the main contributors to the free radical-scavenging activity of the TE. Lipid peroxidation, induced with ascorbate/Fe 2þ , was significantly reduced in the presence of the TE (EC 50 ¼ 26 lg dwb/ml) and fractions containing flavonoids and/or caffeoylquinic acids. The fraction containing flavonoid aglycones was found to be responsible for a major part of the TE protection against lipid peroxidation. Hypericins and hyperforins made no significant contributions to the antioxidant properties of TE. Human consumption of H. perforatum extract or fractions could be beneficial.

No abstract

The inflammatory cytokines interleukin-1␤ and tumor necrosis factor-␣ (TNF-␣) have been identified as mediators of several forms of neurodegeneration in the brain. However, they can produce either deleterious or beneficial effects on neuronal function. We investigated the effects of these cytokines on neuronal death caused by exposure of mouse organotypic hippocampal slice cultures to toxic concentrations of AMPA. Either potentiation of excitotoxicity or neuroprotection was observed, depending on the concentration of the cytokines and the timing of exposure. A relatively high concentration of mouse recombinant TNF-␣ (10 ng/ml) enhanced excitotoxicity when the cultures were simultaneously exposed to AMPA and to this cytokine. Decreasing the concentration of TNF-␣ to 1 ng/ml resulted in neuroprotection against AMPA-induced neuronal death independently on the application protocol. By using TNF-␣ receptor (TNFR) knock-out mice, we demonstrated that the potentiation of AMPA-induced toxicity by TNF-␣ involves TNF receptor-1, whereas the neuroprotective effect is mediated by TNF receptor-2. AMPA exposure was associated with activation and proliferation of microglia as assessed by macrophage antigen-1 and bromodeoxyuridine immunohistochemistry, suggesting a functional recruitment of cytokineproducing cells at sites of neurodegeneration. Together, these findings are relevant for understanding the role of proinflammatory cytokines and microglia activation in acute and chronic excitotoxic conditions.

Tumor necrosis factor (TNF)-␣ has been reported to modulate brain injury, but remarkably, little is known about its effects on neurogenesis. We report that TNF-␣ strongly influences survival, proliferation, and neuronal differentiation in cultured subventricular zone (SVZ) neural stem/progenitor cells derived from the neonatal P1-3 C57BL/6 mice. By using single-cell calcium imaging, we

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA—disseminated and implemented in over 70 countries globally—is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA (Contre les Maladies Chroniques pour un Vieillissement Actif)-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease.

The cognitive reserve is the capacity of the brain to maintain normal performance while exposed to insults or ageing. Increasing evidences point to a role for the interaction between inflammatory conditions and cognitive reserve status during Alzheimer's disease (AD) progression. The production of new neurons along adult life can be considered as one of the components of the cognitive reserve. Interestingly, adult neurogenesis is decreased in mouse models of AD and following inflammatory processes. The aim of this work is to reveal the long-term impact of a systemic inflammatory event on memory and adult neurogenesis in wild type (WT) and triple transgenic mouse model of AD (3xTg-AD). Four month-old mice were intraperitoneally injected once with saline or lipopolysaccharide (LPS) and their performance on spatial memory analyzed with the Morris water maze (MWM) test 7 weeks later. Our data showed that a single intraperitoneal injection with LPS has a long-term impact in the production of hippocampal neurons. Consistently, LPS-treated WT mice showed less doublecortin-positive neurons, less synaptic contacts in newborn neurons, and decreased dendritic volume and complexity. These surprising observations were accompanied with memory deficits. 3xTg-AD mice showed a decrease in new neurons in the dentate gyrus compatible with, although exacerbated, the pattern observed in WT LPS-treated mice. In 3xTg-AD mice, LPS injection did not significantly affected the production of new neurons but reduced their number of synaptic puncta and impaired memory performance, when compared to the observations made in saline-treated 3xTg-AD mice. These data indicate that LPS treatment induces a long-term impairment on hippocampal neurogenesis and memory. Our results show that acute neuroinflammatory events influence the production of new hippocampal neurons, affecting the cognitive reserve and leading to the development of memory deficits associated to AD pathology.

Stroke induces the recruitment of neuronal precursors from the subventricular zone (SVZ) into the ischemic striatum. In injured areas, de-routed neuroblasts use blood vessels as a physical scaffold to their migration, in a process that resembles the constitutive migration seen in the rostral migratory stream (RMS). The molecular mechanism underlying injury-induced vasculature-mediated migration of neuroblasts in the post-stroke striatum remains, however, elusive. Using adult mice we now demonstrate that endothelial cells in the ischemic striatum produce brain-derived neurotrophic factor (BDNF), a neurotrophin that promotes the vasculature-mediated migration of neuronal precursors in the RMS, and that recruited neuroblasts maintain expression of p75NTR, a low-affinity receptor for BDNF. Reactive astrocytes, which are widespread throughout the damaged area, ensheath blood vessels and express TrkB, a high-affinity receptor for BDNF. Despite the absence of BDNF mRNA, we observed strong BDNF immunolabeling in astrocytes, suggesting that these glial cells trap extracellular BDNF. Importantly, this pattern of expression is reminiscent of the adult RMS, where TrkB-expressing astrocytes bind and sequester vasculature-derived BDNF, leading to the entry of migrating cells into the stationary phase. Real-time imaging of cell migration in acute brain slices revealed a direct role for BDNF in promoting the migration of neuroblasts to ischemic areas. We also demonstrated that cells migrating in the ischemic striatum display higher exploratory behavior and longer stationary periods than cells migrating in the RMS. Our findings suggest that the mechanisms involved in the injury-induced vasculature-mediated migration of neuroblasts recapitulate, at least partially, those observed during constitutive migration in the RMS.