Multiple roles of GluN2B-containing NMDA receptors in synaptic plasticity in juvenile hippocampus

AbstractIn the CA1 area of the hippocampus N-methyl-d-aspartate receptors (NMDARs) mediate the induction of long-term depression (LTD), short-term potentiation (STP) and long-term potentiation (LTP). All of these forms of synaptic plasticity can be readily studied in juvenile hippocampal slices but the involvement of particular NMDAR subunits in the induction of these different forms of synaptic plasticity is currently unclear. Here, using NVP-AAM077, Ro 25-6981 and UBP145 to target GluN2A-, 2B- and 2D-containing NMDARs respectively, we show that GluN2B-containing NMDARs (GluN2B) are involved in the induction of LTD, STP and LTP in slices prepared from P14 rat hippocampus. A concentration of Ro (1 μM) that selectively blocks GluN2B-containing diheteromers is able to block LTD. It also inhibits a component of STP without affecting LTP. A higher concentration of Ro (10 μM), that also inhibits GluN2A/B triheteromers, blocks LTP. UBP145 selectively inhibits the Ro-sensitive component of STP whereas NVP inhibits LTP. These data are consistent with a role of GluN2B diheretomers in LTD, a role of both GluN2B- and GluN2D- containing NMDARs in STP and a role of GluN2A/B triheteromers in LTP.This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’

HPV vaccine: an overview of immune response, clinical protection, and new approaches for the future

Although long-term protection is a key-point in evaluating HPV-vaccine over time, there is currently inadequate information on the duration of HPV vaccine-induced immunity and on the mechanisms related to the activation of immune-memory. Longer-term surveillance in a vaccinated population is needed to identify waning immunity, evaluating any requirements for booster immunizations to assess vaccine efficacy against HPV-diseases. Current prophylactic vaccines have the primary end-points to protect against HPV-16 and 18, the genotypes more associated to cervical cancer worldwide. Nevertheless, data from many countries demonstrate the presence, at significant levels, of HPVs that are not included in the currently available vaccine preparations, indicating that these vaccines could be less effective in a particular area of the world. The development of vaccines covering a larger number of HPVs presents the most complex challenge for the future. Therefore, long term immunization and cross-protection of HPV vaccines will be discussed in light of new approaches for the future

Informal Urban Settlements and Cholera Risk in Dar es Salaam, Tanzania

In 2008, for the first time in human history, more than half of the world's population was living in urban areas, and this proportion is expected to increase. As a result of poor economic opportunities and an increasing shortage of affordable housing, much of the spatial growth in many of the world's fastest growing cities is a result of the expansion of informal settlements where residents live without security of tenure and with limited access to basic infrastructure. Although inadequate water and sanitation facilities, crowding, and other poor living conditions can have a significant impact on the spread of infectious diseases, analyses relating these diseases to ongoing global urbanization, especially at the neighborhood and household level in informal settlements, have been infrequent. To begin to address this deficiency, we analyzed urban environmental data and the burden of cholera in Dar es Salaam, Tanzania. We found that cholera incidence was most closely associated with informal housing, population density, and the income level of informal residents. Our analysis suggests that the current growth of many cities in developing countries and expansion of informal settlements will be associated with increased risks to human health, including cholera and other infectious diseases, and underscores the importance of urban planning, resource allocation, and infrastructure placement and management, as the rapidly progressive trend of global urbanization proceeds

Bostonia: The Boston University Alumni Magazine. Volume 7

Founded in 1900, Bostonia magazine is Boston University's main alumni publication, which covers alumni and student life, as well as university activities, events, and programs

Role of Mutagenicity in Asbestos Fiber-Induced Carcinogenicity and Other Diseases

The cellular and molecular mechanisms of how asbestos fibers induce cancers and other diseases are not well understood. Both serpentine and amphibole asbestos fibers have been shown to induce oxidative stress, inflammatory responses, cellular toxicity and tissue injuries, genetic changes, and epigenetic alterations in target cells in vitro and tissues in vivo. Most of these mechanisms are believe to be shared by both fiber-induced cancers and noncancerous diseases. This article summarizes the findings from existing literature with a focus on genetic changes, specifically, mutagenicity of asbestos fibers. Thus far, experimental evidence suggesting the involvement of mutagenesis in asbestos carcinogenicity is more convincing than asbestos-induced fibrotic diseases. The potential contributions of mutagenicity to asbestos-induced diseases, with an emphasis on carcinogenicity, are reviewed from five aspects: (1) whether there is a mutagenic mode of action (MOA) in fiber-induced carcinogenesis; (2) mutagenicity/carcinogenicity at low dose; (3) biological activities that contribute to mutagenicity and impact of target tissue/cell type; (4) health endpoints with or without mutagenicity as a key event; and finally, (5) determinant factors of toxicity in mutagenicity. At the end of this review, a consensus statement of what is known, what is believed to be factual but requires confirmation, and existing data gaps, as well as future research needs and directions, is provided

Megadroughts in the Common Era and the Anthropocene

Exceptional drought events, known as megadroughts, have occurred on every continent outside Antarctica over the past ~2,000 years, causing major ecological and societal disturbances. In this Review, we discuss shared causes and features of Common Era (Year 1–present) and future megadroughts. Decadal variations in sea surface temperatures are the primary driver of megadroughts, with secondary contributions from radiative forcing and land–atmosphere interactions. Anthropogenic climate change has intensified ongoing megadroughts in south-western North America and across Chile and Argentina. Future megadroughts will be substantially warmer than past events, with this warming driving projected increases in megadrought risk and severity across many regions, including western North America, Central America, Europe and the Mediterranean, extratropical South America, and Australia. However, several knowledge gaps currently undermine confidence in understanding past and future megadroughts. These gaps include a paucity of high-resolution palaeoclimate information over Africa, tropical South America and other regions; incomplete representations of internal variability and land surface processes in climate models; and the undetermined capacity of water-resource management systems to mitigate megadrought impacts. Addressing these deficiencies will be crucial for increasing confidence in projections of future megadrought risk and for resiliency planning

Differential modulation of NMDA-stimulated [\u3csup\u3e3\u3c/sup\u3eH]dopamine release from rat striatum by neuropeptide Y and σ receptor ligands

Although the identity of the endogenous ligands for sigma (σ) receptors is unknown, neuropeptide Y (NPY) has been named as a possible candidate for a natural transmitter at these receptors. Using a superfusion system, we compared the effect of NPY on NMDA-stimulated [3H]dopamine release in rat striatum to that of the σ agonists (+)-pentazocine and BD737. In contrast to (+)-pentazocine- or BD737-mediated inhibition of release, NPY enhanced release. However, the same σ antagonists (BD1008, DuP734, haloperidol and DTG) that reverse (+)-pentazocine- or BD737-mediated inhibition, as well as a Y receptor antagonist, PYX-1, all reversed the enhancement. PYX-1 also reversed the (+)-pentazocine- and BD737-mediated inhibition of release. Peptide YY (PYY) and [Leu31,Pro34]NPY did not mimic the effect of NPY. NPY13-36 enhanced release to the same extent as NPY but the effect was not reversed by σ antagonists. Our findings are consistent with the potential role of NPY as an endogenous ligand for a subtype of σ receptor with characteristics different from Y1, Y2 and Y3 receptors but sensitive to PYX-1

Phencyclidine and dizocilpine modulate dopamine release from rat nucleus accumbens via σ receptors

Phencyclidine (PCP) binds to many sites in brain, including PCP receptors located within the N-methyl-D-aspartate (NMDA) receptor-operated cation channel and sigma (σ) receptors. In this study, we compare mechanisms by which PCP, dizocilpine (MK-801), the prototypical σ receptor agonist (+)- pentazocine, and the proposed endogenous σ receptor ligand neuropeptide Y regulate potassium (K+)-stimulated [3H]dopamine release from slices of rat nucleus accumbens. (+)-Pentazocine inhibits K+-stimulated [3H]dopamine release, and neuropeptide Y enhances it. Both effects are blocked by σ1 and neuropeptide Y receptor antagonists, suggesting possible inverse agonism at a subpopulation of σ/neuropeptide Y receptors. In contrast, PCP and MK-801 both enhance K+-stimulated [3H]dopamine release via σ1 and σ2 receptor subtypes, as demonstrated by antagonist sensitivity. Regulation of release by both (+)-pentazocine and neuropeptide Y persists in the presence of tetrodotoxin suggests that the σ/neuropeptide Y receptors mediating the modulation are located presynaptically on dopaminergic nerve terminals, but tetrodotoxin eliminates regulation by PCP and MK-801, suggesting that receptors mediating their effects are located upstream from dopaminergic nerve terminals

Neuropeptide Y-mediated enhancement of NMDA-stimulated [\u3csup\u3e3\u3c/sup\u3eH]dopamine release from rat prefrontal cortex is reversed by σ1 receptor antagonists

Sigma (σ) receptors are located in limbic areas, including the prefrontal cortex, where decreased dopamine levels have been linked to negative symptoms. Although the endogenous ligands for σ receptors are unknown, neuropeptide Y (NPY) has been named as the potential endogenous agonist at these receptors. NPY enhanced NMDA-stimulated [3H]dopamine release in rat prefrontal cortex. This was in contrast to the inhibition produced by the σ agonists (+)pentazocine and BD737. However, four σ antagonists, including one which is σ1 selective, that reverse (+)pentazocine- or BD737-mediated inhibition all reversed the NPY-mediated enhancement. In addition, PYX-1, a Y receptor antagonist, reversed both the (+)pentazocine- and BD737-mediated inhibition and the NPY-mediated enhancement of release. Peptide YY (PYY). [Leu34,Pro34]Npy and NPY13-36, did not mimic the effect of NPY. Our findings are consistent with NPY acting as an endogenous ligand for a subtype of a receptor with characteristics different from Y1, Y2 and Y3 receptors but sensitive to PYX-I. These findings suggest a role for NPY, via σ receptors, as a modulator of dopamine levels in the prefrontal cortex

SH-SY5Y cells as a model for sigma receptor regulation of potassium- stimulated dopamine release

Previous studies in our laboratory using rat brain tissue have shown that neuropeptide Y (NPY) can enhance NMDA- and potassium-stimulated dopamine release from various brain regions and that this enhancement is reversed by sigma (σ) receptor antagonists. In the current study, we sought to determine whether SH-SY5Y cells are suitable for investigating σ receptor effects and whether any σ receptors present are of the subtype responsive to NPY. We compare mechanisms by which the prototypical σ receptor agonist (+)- pentazocine, and the proposed endogenous σ receptor ligand NPY regulate potassium-stimulated [3 H]dopamine release from SH-SY5Y cells. Both (+)- pentazocine and NPY inhibit potassium-stimulated [3 H]dopamine release. Unlike our studies in rat brain tissue, the effect of NPY on [3 H]dopamine release is not reversed by σ receptor antagonists. SH-SY5Y cells appear to be an appropriate model to study the regulation of dopamine release by σ receptors or by NPY receptors, but this population is not identical to that population identified in brain slices. (C) 2000 Elsevier Science B.V