No abstract

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.

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