Pharmacological Analysis of Ionotropic Glutamate Receptor Function in Neuronal Circuits of the Zebrafish Olfactory Bulb

Although synaptic functions of ionotropic glutamate receptors in the olfactory bulb have been studied in vitro, their roles in pattern processing in the intact system remain controversial. We therefore examined the functions of ionotropic glutamate receptors during odor processing in the intact olfactory bulb of zebrafish using pharmacological manipulations. Odor responses of mitral cells and interneurons were recorded by electrophysiology and 2-photon Ca2+ imaging. The combined blockade of AMPA/kainate and NMDA receptors abolished odor-evoked excitation of mitral cells. The blockade of AMPA/kainate receptors alone, in contrast, increased the mean response of mitral cells and decreased the mean response of interneurons. The blockade of NMDA receptors caused little or no change in the mean responses of mitral cells and interneurons. However, antagonists of both receptor types had diverse effects on the magnitude and time course of individual mitral cell and interneuron responses and, thus, changed spatio-temporal activity patterns across neuronal populations. Oscillatory synchronization was abolished or reduced by AMPA/kainate and NMDA receptor antagonists, respectively. These results indicate that (1) interneuron responses depend mainly on AMPA/kainate receptor input during an odor response, (2) interactions among mitral cells and interneurons regulate the total olfactory bulb output activity, (3) AMPA/kainate receptors participate in the synchronization of odor-dependent neuronal ensembles, and (4) ionotropic glutamate receptor-containing synaptic circuits shape odor-specific patterns of olfactory bulb output activity. These mechanisms are likely to be important for the processing of odor-encoding activity patterns in the olfactory bulb

Specificity and Actions of an Arylaspartate Inhibitor of Glutamate Transport at the Schaffer Collateral-CA1 Pyramidal Cell Synapse

In this study we characterized the pharmacological selectivity and physiological actions of a new arylaspartate glutamate transporter blocker, L-threo-ß-benzylaspartate (L-TBA). At concentrations up to 100 µM, L-TBA did not act as an AMPA receptor (AMPAR) or NMDA receptor (NMDAR) agonist or antagonist when applied to outside-out patches from mouse hippocampal CA1 pyramidal neurons. L-TBA had no effect on the amplitude of field excitatory postsynaptic potentials (fEPSPs) recorded at the Schaffer collateral-CA1 pyramidal cell synapse. Excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons were unaffected by L-TBA in the presence of physiological extracellular Mg2+ concentrations, but in Mg2+-free solution, EPSCs were significantly prolonged as a consequence of increased NMDAR activity. Although L-TBA exhibited approximately four-fold selectivity for neuronal EAAT3 over glial EAAT1/EAAT2 transporter subtypes expressed in Xenopus oocytes, the L-TBA concentration-dependence of the EPSC charge transfer increase in the absence of Mg2+ was the same in hippocampal slices from EAAT3 +/+ and EAAT3 −/− mice, suggesting that TBA effects were primarily due to block of glial transporters. Consistent with this, L-TBA blocked synaptically evoked transporter currents in CA1 astrocytes with a potency in accord with its block of heterologously expressed glial transporters. Extracellular recording in the presence of physiological Mg2+ revealed that L-TBA prolonged fEPSPs in a frequency-dependent manner by selectively increasing the NMDAR-mediated component of the fEPSP during short bursts of activity. The data indicate that glial glutamate transporters play a dominant role in limiting extrasynaptic transmitter diffusion and binding to NMDARs. Furthermore, NMDAR signaling is primarily limited by voltage-dependent Mg2+ block during low-frequency activity, while the relative contribution of transport increases during short bursts of higher frequency signaling

Astrocyte-mediated short-term synaptic depression in the rat hippocampal CA1 area: two modes of decreasing release probability

<p>Abstract</p> <p>Background</p> <p>Synaptic burst activation feeds back as a short-term depression of release probability at hippocampal CA3-CA1 synapses. This short-term synaptic plasticity requires functional astrocytes and it affects both the recently active (< 1 s) synapses (post-burst depression) as well as inactive neighboring synapses (transient heterosynaptic depression). The aim of this study was to investigate and compare the components contributing to the depression of release probability in these two different scenarios.</p> <p>Results</p> <p>When tested using paired-pulses, following a period of inactivity, the transient heterosynaptic depression was expressed as a reduction in the response to only the first pulse, whereas the response to the second pulse was unaffected. This selective depression of only the first response in a high-frequency burst was shared by the homosynaptic post-burst depression, but it was partially counteracted by augmentation at these recently active synapses. In addition, the expression of the homosynaptic post-burst depression included an astrocyte-mediated reduction of the pool of release-ready primed vesicles.</p> <p>Conclusions</p> <p>Our results suggest that activated astrocytes depress the release probability via two different mechanisms; by depression of vesicular release probability only at inactive synapses and by imposing a delay in the recovery of the primed pool of vesicles following depletion. These mechanisms restrict the expression of the astrocyte-mediated depression to temporal windows that are typical for synaptic burst activity.</p

A Glial Variant of the Vesicular Monoamine Transporter Is Required To Store Histamine in the Drosophila Visual System

Unlike other monoamine neurotransmitters, the mechanism by which the brain's histamine content is regulated remains unclear. In mammals, vesicular monoamine transporters (VMATs) are expressed exclusively in neurons and mediate the storage of histamine and other monoamines. We have studied the visual system of Drosophila melanogaster in which histamine is the primary neurotransmitter released from photoreceptor cells. We report here that a novel mRNA splice variant of Drosophila VMAT (DVMAT-B) is expressed not in neurons but rather in a small subset of glia in the lamina of the fly's optic lobe. Histamine contents are reduced by mutation of dVMAT, but can be partially restored by specifically expressing DVMAT-B in glia. Our results suggest a novel role for a monoamine transporter in glia that may be relevant to histamine homeostasis in other systems

Occurrence of mental illness following prenatal and early childhood exposure to tetrachloroethylene (PCE)-contaminated drinking water: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>While many studies of adults with solvent exposure have shown increased risks of anxiety and depressive disorders, there is little information on the impact of prenatal and early childhood exposure on the subsequent risk of mental illness. This retrospective cohort study examined whether early life exposure to tetrachloroethylene (PCE)-contaminated drinking water influenced the occurrence of depression, bipolar disorder, post-traumatic stress disorder, and schizophrenia among adults from Cape Cod, Massachusetts.</p> <p>Methods</p> <p>A total of 1,512 subjects born between 1969 and 1983 were studied, including 831 subjects with both prenatal and early childhood PCE exposure and 547 unexposed subjects. Participants completed questionnaires to gather information on mental illnesses, demographic and medical characteristics, other sources of solvent exposure, and residences from birth through 1990. PCE exposure originating from the vinyl-liner of water distribution pipes was assessed using water distribution system modeling software that incorporated a leaching and transport algorithm.</p> <p>Results</p> <p>No meaningful increases in risk ratios (RR) for depression were observed among subjects with prenatal and early childhood exposure (RR: 1.1, 95% CI: 0.9-1.4). However, subjects with prenatal and early childhood exposure had a 1.8-fold increased risk of bipolar disorder (N = 36 exposed cases, 95% CI: 0.9-1.4), a 1.5-fold increased risk post-traumatic stress disorder (N = 47 exposed cases, 95% CI: 0.9-2.5), and a 2.1-fold increased risk of schizophrenia (N = 3 exposed cases, 95% CI: 0.2-20.0). Further increases in the risk ratio were observed for bipolar disorder (N = 18 exposed cases, RR; 2.7, 95% CI: 1.3-5.6) and post-traumatic stress disorder (N = 18 exposed cases, RR: 1.7, 95% CI: 0.9-3.2) among subjects with the highest exposure levels.</p> <p>Conclusions</p> <p>The results of this study provide evidence against an impact of early life exposure to PCE on the risk of depression. In contrast, the results provide support for an impact of early life exposure on the risk of bipolar disorder and post-traumatic stress disorder. The number of schizophrenia cases was too small to draw reliable conclusions. These findings should be confirmed in investigations of other similarly exposed populations.</p

Feedforward Inhibition and Synaptic Scaling – Two Sides of the Same Coin?

Feedforward inhibition and synaptic scaling are important adaptive processes that control the total input a neuron can receive from its afferents. While often studied in isolation, the two have been reported to co-occur in various brain regions. The functional implications of their interactions remain unclear, however. Based on a probabilistic modeling approach, we show here that fast feedforward inhibition and synaptic scaling interact synergistically during unsupervised learning. In technical terms, we model the input to a neural circuit using a normalized mixture model with Poisson noise. We demonstrate analytically and numerically that, in the presence of lateral inhibition introducing competition between different neurons, Hebbian plasticity and synaptic scaling approximate the optimal maximum likelihood solutions for this model. Our results suggest that, beyond its conventional use as a mechanism to remove undesired pattern variations, input normalization can make typical neural interaction and learning rules optimal on the stimulus subspace defined through feedforward inhibition. Furthermore, learning within this subspace is more efficient in practice, as it helps avoid locally optimal solutions. Our results suggest a close connection between feedforward inhibition and synaptic scaling which may have important functional implications for general cortical processing

Using European travellers as an early alert to detect emerging pathogens in countries with limited laboratory resources

BACKGROUND: The volume, extent and speed of travel have dramatically increased in the past decades, providing the potential for an infectious disease to spread through the transportation network. By collecting information on the suspected place of infection, existing surveillance systems in industrialized countries may provide timely information for areas of the world without adequate surveillance currently in place. We present the results of a case study using reported cases of Shigella dysenteriae serotype 1 (Sd1) in European travellers to detect "events" of Sd1, related to either epidemic cases or endemic cases in developing countries. METHODS: We identified papers from a Medline search for reported events of Sd1 from 1940 to 2002. We requested data on shigella infections reported to the responsible surveillance entities in 17 European countries. Reports of Sd1 from the published literature were then compared with Sd1 notified cases among European travellers from 1990 to 2002. RESULTS: Prior to a large epidemic in 1999–2000, no cases of Sd1 had been identified in West Africa. However, if travellers had been used as an early warning, Sd1 could have been identified in this region as earlier as 1992. CONCLUSION: This project demonstrates that tracking diseases in European travellers could be used to detect emerging disease in developing countries. This approach should be further tested with a view to the continuous improvement of national health surveillance systems and existing European networks, and may play a significant role in aiding the international public health community to improve infectious disease control