Vector supersymmetry in topological field theories

We present a simple derivation of vector supersymmetry transformations for topological field theories of Schwarz- and Witten-type. Our method is similar to the derivation of BRST-transformations from the so-called horizontality conditions or Russian formulae. We show that this procedure reproduces in a concise way the known vector supersymmetry transformations of various topological models and we use it to obtain some new transformations of this type for 4d topological YM-theories in different gauges.Comment: 19 page

Remarks on Topological SUSY in sixdimensional TQFTs

We establish the existence of the topological vector supersymmetry in the six dimensional topological field theory for two-form fields introduced by Baulieu and West. We investigate the relation of these symmetries to the twist operation for the (2,0) supersymmetry and comment on their resemblance to the analogous symmetries in topological Yang-Mills theory.Comment: 12 pages, to be published in JHEP 11(1999)03

Interacting six-dimensional topological field theories

We study the gauge-fixing and symmetries (BRST-invariance and vector supersymmetry) of various six-dimensional topological models involving Abelian or non-Abelian 2-form potentials.Comment: 11 page

Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monoxygenase (KMO) deletion or galantamine

Glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100 mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70-kDa and 100-kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(−/−) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development

Prenatal inhibition of the tryptophan–kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus

Glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) are important in early brain development, influencing cell proliferation and migration, neuritogenesis, axon guidance and synapse formation. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Rats were treated in late gestation with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]-benzene-sulphonamide (Ro61-8048), an inhibitor of kynurenine-3-monoxygenase which diverts kynurenine metabolism to kynurenic acid. Within 5 h of drug administration, there was a significant decrease in GluN2A expression and increased GluN2B in the embryo brains, with changes in sonic hedgehog at 24 h. When injected dams were allowed to litter normally, the brains of offspring were removed at postnatal day 21 (P21). Recordings of hippocampal field excitatory synaptic potentials (fEPSPs) showed that prenatal exposure to Ro61-8048 increased neuronal excitability and paired-pulse facilitation. Long-term potentiation was also increased, with no change in long-term depression. At this time, levels of GluN2A, GluN2B and postsynaptic density protein PSD-95 were all increased. Among several neurodevelopmental proteins, the expression of sonic hedgehog was increased, but DISC1 and dependence receptors were unaffected, while raised levels of doublecortin and Proliferating Cell Nuclear Antigen (PCNA) suggested increased neurogenesis. The results reveal that inhibiting the kynurenine pathway in utero leads to molecular and functional synaptic changes in the embryos and offspring, indicating that the pathway is active during gestation and plays a significant role in the normal early development of the embryonic and neonatal nervous system

Topological field theories and their symmetries within the Batalin-Vilkovisky framework

We discuss the algebraic construction of topological models (of both Schwarz- and Witten-type) within the Batalin-Vilkovisky formalism and we elaborate on a simple description of vector supersymmetry within this framework

Symmetries of topological field theories in the BV-framework

Topological field theories of Schwarz-type generally admit symmetries whose algebra does not close off-shell, e.g. the basic symmetries of BF models or vector supersymmetry of the gauge-fixed action for Chern-Simons theory (this symmetry being at the origin of the perturbative finiteness of the theory). We present a detailed discussion of all these symmetries within the algebraic approach to the Batalin-Vilkovisky formalism. Moreover, we discuss the general algebraic construction of topological models of both Schwarz- and Witten-type.Comment: 30 page

Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway

During early brain development, N-methyl-d-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog

Kynurenine pathway metabolism following prenatal KMO inhibition and in Mecp2+/- mice, using liquid chromatography-tandem mass spectrometry

To quantify the full range of tryptophan metabolites along the kynurenine pathway, a liquid chromatography – tandem mass spectrometry method was developed and used to analyse brain extracts of rodents treated with the kynurenine-3-mono-oxygenase (KMO) inhibitor Ro61-8048 during pregnancy. There were significant increases in the levels of kynurenine, kynurenic acid, anthranilic acid and 3-hydroxy-kynurenine (3-HK) in the maternal brain after 5 h but not 24 h, while the embryos exhibited high levels of kynurenine, kynurenic acid and anthranilic acid after 5 h which were maintained at 24 h post-treatment. At 24 h there was also a strong trend to an increase in quinolinic acid levels (P = 0.055). No significant changes were observed in any of the other kynurenine metabolites. The results confirm the marked increase in the accumulation of some neuroactive kynurenines when KMO is inhibited, and re-emphasise the potential importance of changes in anthranilic acid. The prolonged duration of metabolite accumulation in the embryo brains indicates a trapping of compounds within the embryonic CNS independently of maternal levels. When brains were examined from young mice heterozygous for the meCP2 gene – a potential model for Rett syndrome - no differences were noted from control mice, suggesting that the proposed roles for kynurenines in autism spectrum disorder are not relevant to Rett syndrome, supporting its recognition as a distinct, independent, condition

Prenatal activation of toll-like receptors-3 by administration of the viral mimetic poly(I:C) changes synaptic proteins, N-methyl-D-aspartate receptors and neurogenesis markers in offspring

Background - There is mounting evidence for a neurodevelopmental basis for disorders such as autism and schizophrenia, in which prenatal or early postnatal events may influence brain development and predispose the young to develop these and related disorders. We have now investigated the effect of a prenatal immune challenge on brain development in the offspring. Pregnant rats were treated with the double-stranded RNA polyinosinic:polycytidylic acid (poly(I:C); 10 mg/kg) which mimics immune activation occurring after activation of Toll-like receptors-3 (TLR3) by viral infection. Injections were made in late gestation (embryonic days E14, E16 and E18), after which parturition proceeded naturally and the young were allowed to develop up to the time of weaning at postnatal day 21 (P21). The brains of these animals were then removed to assess the expression of 13 different neurodevelopmental molecules by immunoblotting. Results - Measurement of cytokine levels in the maternal blood 5 hours after an injection of poly(I:C) showed significantly increased levels of monocyte chemoattractant protein-1 (MCP-1), confirming immune activation. In the P21 offspring, significant changes were detected in the expression of GluN1 subunits of NMDA receptors, with no difference in GluN2A or GluN2B subunits or the postsynaptic density protein PSD-95 and no change in the levels of the related small GTPases RhoA or RhoB, or the NMDA receptor modulator EphA4. Among presynaptic molecules, a significant increase in Vesicle Associated Membrane Protein-1 (VAMP-1; synaptobrevin) was seen, with no change in synaptophysin or synaptotagmin. Proliferating Cell Nuclear Antigen (PCNA), as well as the neurogenesis marker doublecortin were unchanged, although Sox-2 levels were increased, suggesting possible changes in the rate of new cell differentiation. Conclusions - The results reveal the induction by prenatal poly(I:C) of selective molecular changes in the brains of P21 offspring, affecting primarily molecules associated with neuronal development and synaptic transmission. These changes may contribute to the behavioural abnormalities that have been reported in adult animals after exposure to poly(I:C) and which resemble symptoms seen in schizophrenia and related disorders