A Postsynaptic Mechanism of Zinc Transport Driving Inhibition of NMDA Receptors

Zinc is an essential element with diverse signaling functions in the central nervous system. Extracellular zinc acts on a variety of receptors to modulate neurotransmission. Notably, zinc binds and inhibits the GluN2A subunit of NMDA receptors (NMDARs) with high affinity. Inside the cell, zinc also triggers diverse signaling cascades, ranging from zinc-induced gene expression to cell death triggered by high concentrations of zinc. To maintain sufficient signaling without tipping the scales towards cell death, a complex system of transporters, metalloproteins, and ion channels regulate the localization and concentration of zinc. The zinc transporter, ZnT3, concentrates the majority of loosely bound ‘labile’ zinc into synaptic vesicles from where it then is released into the cleft in an activity-dependent manner. Current modeling of vesicular zinc assumes that ZnT3-dependent zinc is released and subsequently diffuses across the cleft and this is sufficient to account for its actions on postsynaptic targets, including NMDARs. Interestingly, the transporter ZnT1 is located in the postsynaptic density and binds directly to the GluN2A subunit of NMDARs, suggesting that ZnT1’s transport of zinc out of the cytoplasm into the extracellular space may contribute to NMDAR inhibition. This suggests that ZnT1 and intracellular zinc may critically regulate zinc inhibition of NMDARs through ZnT1’s interaction with GluN2A. To explore this question, we developed a novel peptide that specifically disrupts the interaction between GluN2A and ZnT1. We found that either disrupting ZnT1’s association with GluN2A or chelating intracellular zinc is sufficient to block endogenous inhibition of NMDARs, even in the presence of presynaptic zinc release. ZnT1, in addition to transporting cytosolic zinc, is also upregulated by intracellular zinc through the metal regulatory transcription factor 1. We found that increasing intracellular zinc is sufficient to drive upregulation of ZnT1-GluN2A interactions and subsequent inhibition of NMDARs. Together these data reveal a novel mechanism in which presynaptic release, intracellular zinc, and ZnT1 cooperatively drive inhibition of NMDARs. These findings add complexity to our current understanding of zinc dynamics at the synapses and provide a novel mechanism for modulating zinc and NMDAR signaling

Population Dynamics Based on Resource Availability & Founding Effects: Live & Computational Models

With the looming global population crisis, it is more important now than ever that students understand what factors influence population dynamics. We present three learning modules with authentic, student-centered investigations that explore rates of population growth and the importance of resources. These interdisciplinary modules integrate biology, mathematics, and computer-literacy concepts aligned with the Next Generation Science Standards. The activities are appropriate for middle and high school science classes and for introductory college-level biology courses. The modules incorporate experimentation, data collection and analysis, drawing conclusions, and application of studied principles to explore factors affecting population dynamics in fruit flies. The variables explored include initial population structure, food availability, and space of the enclosed population. In addition, we present a computational simulation in which students can alter the same variables explored in the live experimental modules to test predictions on the consequences of altering the variables. Free web-based graphing (Joinpoint) and simulation software (NetLogo) allows students to work at home or at school

Food site residence time and female competitive relationships in wild gray-cheeked mangabeys (Lophocebus albigena)

Authors of socioecological models propose that food distribution affects female social relationships in that clumped food resources, such as fruit, result in strong dominance hierarchies and favor coalition formation with female relatives. A number of Old World monkey species have been used to test predictions of the socioecological models. However, arboreal forest-living Old World monkeys have been understudied in this regard, and it is legitimate to ask whether predominantly arboreal primates living in tropical forests exhibit similar or different patterns of behavior. Therefore, the goal of our study was to investigate female dominance relationships in relation to food in gray-cheeked mangabeys (Lophocebus albigena). Since gray-cheeked mangabeys are largely frugivorous, we predicted that females would have linear dominance hierarchies and form coalitions. In addition, recent studies suggest that long food site residence time is another important factor in eliciting competitive interactions. Therefore, we also predicted that when foods had long site residence times, higher-ranking females would be able to spend longer at the resource than lower-ranking females. Analyses showed that coalitions were rare relative to some other Old World primate species, but females had linear dominance hierarchies. We found that, contrary to expectation, fruit was not associated with more agonism and did not involve long site residence times. However, bark, a food with a long site residence time and potentially high resource value, was associated with more agonism, and higher-ranking females were able to spend more time feeding on it than lower-ranking females. These results suggest that higher-ranking females may benefit from higher food and energy intake rates when food site residence times are long. These findings also add to accumulating evidence that food site residence time is a behavioral contributor to female dominance hierarchies in group-living species

Hyperpolarization Induced by Lipopolysaccharides but Not by Chloroform Is Inhibited by Doxapram, an Inhibitor of Two-P-Domain K⁺ Channel (K2P)

Bacterial septicemia is commonly induced by Gram-negative bacteria. The immune response is triggered in part by the secretion of bacterial endotoxin lipopolysaccharide (LPS). LPS induces the subsequent release of inflammatory cytokines which can result in pathological conditions. There is no known blocker to the receptors of LPS. The Drosophila larval muscle is an amendable model to rapidly screen various compounds that affect membrane potential and synaptic transmission such as LPS. LPS induces a rapid hyperpolarization in the body wall muscles and depolarization of motor neurons. These actions are blocked by the compound doxapram (10 mM), which is known to inhibit a subtype of the two-P-domain K+ channel (K2P channels). However, the K2P channel blocker PK-THPP had no effect on the Drosophila larval muscle at 1 and 10 mM. These channels are activated by chloroform, which also induces a rapid hyperpolarization of these muscles, but the channels are not blocked by doxapram. Likewise, chloroform does not block the depolarization induced by doxapram. LPS blocks the postsynaptic glutamate receptors on Drosophila muscle. Pre-exposure to doxapram reduces the LPS block of these ionotropic glutamate receptors. Given that the larval Drosophila body wall muscles are depolarized by doxapram and hyperpolarized by chloroform, they offer a model to begin pharmacological profiling of the K2P subtype channels with the potential of identifying blockers for the receptors to mitigate the actions of the Gram-negative endotoxin LPS

Effective field theory and keV lines from dark matter

We survey operators that can lead to a keV photon line from dark matter decay or annihilation. We are motivated in part by recent claims of an unexplained 3.5 keV line in galaxy clusters and in Andromeda, but our results could apply to any hypothetical line observed in this energy range. We find that given the amount of flux that is observable, explanations in terms of decay are more plausible than annihilation, at least if the annihilation is directly to Standard Model states rather than intermediate particles. The decay case can be explained by a scalar or pseudoscalar field coupling to photons suppressed by a scale not far below the reduced Planck mass, which can be taken as a tantalizing hint of high-scale physics. The scalar case is particularly interesting from the effective field theory viewpoint, and we discuss it at some length. Because of a quartically divergent mass correction, naturalness strongly suggests the theory should be cut off at or below the 1000 TeV scale. The most plausible such natural UV completion would involve supersymmetry. These bottom-up arguments reproduce expectations from top-down considerations of the physics of moduli. A keV line could also arise from the decay of a sterile neutrino, in which case a renormalizable UV completion exists and no direct inference about high-scale physics is possiblePhysic