Spike timing,calcium signals and synaptic plasticity

Plasticity at central synapses depends critically on the timing of presynaptic and postsynaptic action potentials. Key initial steps in synaptic plasticity involve the back-propagation of action potentials into the dendritic tree and calcium influx that depends nonlinearly on the action potential and synaptic input. These initial steps are now better understood. In addition, recent studies of processes as diverse as gene expression and channel inactivation suggest that responses to calcium transients depend not only their amplitude, but on their time course and on the location of their origin.     

Cellular signalling: STIMulating calcium entry

The molecular identity of the signal coupling intracellular Ca(2+) store depletion to the activation of Ca(2+) entry has long resisted exposure. Two recent studies independently implicate the STIM protein family as essential components in this coupling. These data provide new impetus to resolve how store Ca(2+) content is sensed and communicated to store-operated Ca(2+) channels at the cell surface.     

Cellular calcium and atherosclerosis: A brief review

Evidence for and against the theory that cell calcium is causally involved in the pathogenesis of atherosclerosis is presented and evaluated. In particular, it is argued that: (1) arterial calcium is increased in atherosclerosis; (2) this increase in tissue calcium content is largely intracellular; (3) this increased intracellular calcium content is caused by increased plasma membrane calcium permeability; (4) the increased calcium content is causally related to atherogenesis; (5) many of the cell physiological, cell biological, biochemical, and molecular biological processes, known to function abnormally in atherosclerosis, are also known to be calcium regulated; and (6) these processes are activated or inactivated in atherosclerosis in a manner consistent with increased cell calcium. It is concluded that the calcium-atherogenesis hypothesis has the potential to unify macroscopic clinical risk factors in terms of intracellular mechanisms that are controlled by cell calcium, and that this hypothesis deserves further experimental tests.     

Transmembrane calcium current: Mechanism,registration procedures,calcium-mediated modulators of synaptic transmission

The paper reviews data on mechanisms of calcium current and methods of its recording. The involvement of calcium ions in excitation of nerve and muscle cells and in particular in synaptic transmission processes is considered. Calcium signaling relies on voltage-dependent and ligand-gated calcium channels. The review focuses mainly on calcium currents flowing through voltage-dependent channels. The conditions evoking calcium currents, basic methods of their recordings, as well as effects of some important endogenous modulators of neuromuscular transmission are overviewed.     

Decoding cortical neuronal signals: Network models,information estimation and spatial tuning

We have studied the encoding of spatial pattern information by complex cells in the primary visual cortex of awake monkeys. Three models for the conditional probabilities of different stimuli, given the neuronal response, were fit and compared using cross-validation. For our data, a feed-forward neural network proved to be the best of these models.The information carried by a cell about a stimulus set can be calculated from the estimated conditional probabilities. We performed a spatial spectroscopy of the encoding, examining how the transmitted information varies with both the average coarseness of the stimulus set and the coarseness differences within it. We find that each neuron encodes information about many features at multiple scales. Our data do not appear to allow a characterization of these variations in terms of the detection of simple single features such as oriented bars.     

The plant vacuole: emitter and receiver of calcium signals

This review portrays the plant vacuole as both a source and a target of Ca²⁺ signals. In plants, the vacuole represents a Ca²⁺ store of enormous size and capacity. Total and free Ca²⁺ concentrations in the vacuole vary with plant species, cell type, and environment, which is likely to have an impact on vacuolar function and the release of vacuolar Ca²⁺. It is known that cytosolic Ca²⁺ signals are often generated by release of the ion from internal stores, but in very few cases has a role of the vacuole been directly demonstrated. Biochemical and electrophysical studies have provided evidence for the operation of ligand- and voltage-gated Ca²⁺-permeable channels in the vacuolar membrane. The underlying molecular mechanisms are largely unknown with one exception: the slow vacuolar channel, encoded by TPC1, is the only vacuolar Ca²⁺-permeable channel cloned to date. However, due to its complex regulation and its low selectivity amongst cations, the role of this channel in Ca²⁺ signalling is still debated. Many transport proteins at the vacuolar membrane are also targets of Ca²⁺ signals, both by direct binding of Ca²⁺ and by Ca²⁺-dependent phosphorylation. This enables the operation of feedback mechanisms and integrates vacuolar transport systems in the wider signalling network of the plant cell.     

Cellular organization of normal mouse liver: a histological,quantitative immunocytochemical,and fine structural analysis

The cellular organization of normal mouse liver was studied using light and electron microscopy and quantitative immunocytochemical techniques. The general histological organization of the mouse liver is similar to livers of other mammalian species, with a lobular organization based on the distributions of portal areas and central venules. The parenchymal hepatocytes were detected with immunocytochemical techniques to recognize albumin or biotin containing cells. The macrophage Kupffer cells were identified with F4-80 immunocytochemistry, Ito stellate cells were identified with GFAP immunocytochemistry, and endothelial cells were labeled with the CD-34 antibody. Kupffer cells were labeled with intravascularly administered fluorescently labeled latex microspheres of both large (0.5 μm) and small (0.03 μm) diameters, while endothelial cells were labeled only with small diameter microspheres. Neither hepatocytes nor Ito stellate cells were labeled by intravascularly administered latex microspheres. The principal fine structural features of hepatocytes and non-parenchymal cells of mouse liver are similar to those reported for rat. Counts of immunocytochemically labeled cells with stained nuclei indicated that hepatocytes constituted approximately 52% of all labeled cells, Kupffer cells about 18%, Ito cells about 8%, and endothelial cells about 22% of all labeled cells. Approximately, 35% of the hepatocytes contained two nuclei; none of the Kupffer or Ito cells were double nucleated. The presence of canaliculi and a bile duct system appear similar to that reported for other species. The cellular organization of the mouse liver is quite similar to that of other mammalian species, confirming that the mouse presents a useful animal model for studies of liver structure and function.     

Cellular mechanisms controlling light-stimulated gravitropism: role of calcium

An irradiation with visible light can alter the gravitropic responsiveness of shoots and roots. This indicates that light must affect some biochemical process in plant cells which is the same as, or importantly influences, a biochemical process that regulates gravitropism. In many cases, the light receptor for this effect is the pigment phytochrome, which initiates a variety of important photomorphogenic responses in plants. Recent results suggest that both gravistimulation and phytochrome photoactivation result in altered Ca²⁺ transport into and out of the affected cells. This article reviews the evidence that these Ca²⁺ fluxes may be the common biochemical process which modulates both gravitropism and photomorphogenesis.     

Determining zinc with commonly used calcium and zinc fluorescent indicators, a question on calcium signals

Investigations into the roles of Ca(2+) and Zn(2+) in cell biology have been facilitated by the development of sensitive fluorometric probes that have enabled the measurement of Ca(2+) or Zn(2+) in both extracellular and intracellular environments. It is critical to be aware of the specificity and relative selectivity of a probe for the targeted ion. Here, we investigated metal-ion responses by screening nominally Zn(2+)- or Ca(2+)-selective fluorophores in solutions containing various concentrations of Ca(2+), as a potential interferent for Zn(2+), or Zn(2+), as a potential interferent for Ca(2+). The results suggested that Zn(2+)-sensitive dyes were more specific for their targeted ion than dyes that targeted Ca(2+). Ca(2+)-sensitive dyes such as Calcium Green-1, Fura-2, and Fluo-3 showed a wide range of interaction with Zn(2+), even responding to Zn(2+) in the presence of high concentrations of Ca(2+). We demonstrate that these Ca(2+) indicators can effectively measure dynamic changes of cytosolic Zn(2+). Our results appeal for a new generation of Ca(2+) fluorophores that are more specific for Ca(2+) over Zn(2+). One implication of these results is that data obtained using Ca(2+)-sensitive dyes may need to be re-examined to determine if results previously attributed to Ca(2+) could, in part, be due to Zn(2+).     

Multi-target novel neuroprotective compound ITH33/IQM9.21 inhibits calcium entry, calcium signals and exocytosis

Compound ITH33/IQM9.21 (ITH/IQM) belongs to a new family of l-glutamic acid derivatives with antioxidant and neuroprotective properties on in vitro and in vivo models of stroke. Because neuronal damage after brain ischemia is tightly linked to excess Ca²⁺ entry and neuronal Ca²⁺ overload, we have investigated whether compound ITH/IQM antagonises the elevations of the cytosolic Ca²⁺ concentrations ([Ca²⁺]_c) and the ensuing exocytotic responses triggered by depolarisation of bovine chromaffin cells. In fluo-4-loaded cell populations, ITH/IQM reduced the K⁺-evoked [Ca²⁺]_c transients with an IC₅₀ of 5.31 μM. At 10 μM, the compound decreased the amplitude and area of the Ca²⁺ transient elicited by challenging single fura-2-loaded cells with high K⁺, by 40% and 80%, respectively. This concentration also caused a blockade of K⁺-induced catecholamine release at the single-cell level (78%) and cell populations (55%). These effects are likely due to blockade of the whole-cell inward Ca²⁺ currents (IC₅₀ = 6.52 μM). At 10 μM, ITH/IQM also inhibited the Ca²⁺-dependent outward K⁺ current, leaving untouched the voltage-dependent component of I_K. The inward Na⁺ current was unaffected. Inhibition of depolarisation-elicited Ca²⁺ entry, [Ca²⁺]_c elevation and exocytosis could contribute to the neuroprotective effects of ITH/IQM in vulnerable neurons undergoing depolarisation during brain ischemia.     

Presynaptic calcium signals during neurotransmitter release: detection with fluorescent indicators and other calcium chelators.

Synthetic calcium buffers, including fluorescent calcium indicators, were microinjected into squid 'giant' presynaptic nerve terminals to investigate the calcium signal that triggers neurotransmitter secretion. Digital imaging methods, applied in conjunction with the fluorescent calcium indicator dye fura-2, reveal that transient rises in presynaptic calcium concentration are associated with action potentials. Transmitter release terminates within 1-2 ms after a train of action potentials, even though presynaptic calcium concentration remains at micromolar levels for many seconds longer. Microinjection of the calcium buffer, EGTA, into the presynaptic terminal has no effect on transmitter release evoked by single presynaptic action potentials. EGTA injection does, however, block the change in calcium concentration measured by fura-2. Therefore, the calcium signal measured by fura-2 is not responsible for triggering release. These results suggest that the rise in presynaptic calcium concentration that triggers release must be highly localized to escape detection with fura-2 imaging. Unlike EGTA, microinjection of BAPTA--a calcium buffer with an equilibrium affinity for calcium similar to that of EGTA--produces a potent, dose-dependent, and reversible block of action-potential evoked transmitter release. The superior ability of BAPTA to block transmitter release apparently is due to the more rapid calcium-binding kinetics of BAPTA compared to EGTA. Because EGTA should bind calcium within a few tens of microseconds under the conditions of our experiments, the inability of EGTA to block release indicates that transmitter release is triggered within a few tens of microseconds after the entry of calcium into the presynaptic terminal.(ABSTRACT TRUNCATED AT 250 WORDS)     

The nature and identification of quantitative trait loci: a community's view

This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?     

Drosophila bristles and the nature of quantitative genetic variation

Numbers of Drosophila sensory bristles present an ideal model system to elucidate the genetic basis of variation for quantitative traits. Here, we review recent evidence that the genetic architecture of variation for bristle numbers is surprisingly complex. A substantial fraction of the Drosophila genome affects bristle number, indicating pervasive pleiotropy of genes that affect quantitative traits. Further, a large number of loci, often with sex- and environment-specific effects that are also conditional on background genotype, affect natural variation in bristle number. Despite this complexity, an understanding of the molecular basis of natural variation in bristle number is emerging from linkage disequilibrium mapping studies of individual candidate genes that affect the development of sensory bristles. We show that there is naturally segregating genetic variance for environmental plasticity of abdominal and sternopleural bristle number. For abdominal bristle number this variance can be attributed in part to an abnormal abdomen-like phenotype that resembles the phenotype of mutants defective in catecholamine biosynthesis. Dopa decarboxylase (Ddc) encodes the enzyme that catalyses the final step in the synthesis of dopamine, a major Drosophila catecholamine and neurotransmitter. We found that molecular polymorphisms at Ddc are indeed associated with variation in environmental plasticity of abdominal bristle number.     

The tooting and quacking vibration signals of honeybee queens: a quantitative analysis

Summary The behaviour of young honeybee queens and of worker bees was studied in an observation hive. Tooting and quacking signals emitted by the queens were recorded as airborne sound and as substrate vibrations of the combs by means of a microphone and a laser vibrometer, respectively. The fundamental frequency component is larger than the harmonics when the signals are measured as vibration velocity, and it is argued that the signals are carried mainly by the fundamental frequency component. The frequencies emitted depend on the queens' age, and the tooting syllables contain a frequency sweep. These observations may explain some of the very diverse frequency values reported in the literature. The fundamental carrier frequencies of the toots and quacks overlap, but the tooting syllables have longer rise times than the quacking syllables. Recordings of the vibration of cells in which queens were confined allowed us to measure the threshold for the release of quacking in the confined queens by artificial toots and by natural toots from emerged queens. Artificial toots with long syllable rise time are more efficient in releasing quacking responses than are toots with short syllable rise time. This observation may suggest that the bees recognize these signals mainly by their temporal structure. A comparison of the threshold, emission level, and attenuation with distance, suggests that these and other vibration signals are used by honey bees only for local communication within a restricted area of the comb.