bluuebunny/crossref_metadata_2025 huggingface dataset:
Asset Markets and Equilibrium Selection in Public Goods Games with Provision Points: An Experimental Study
Authors: Broseta Bruno , Fatas Enrique , Neugebauer Tibor
Published: September 2003

We report experimental results on the effects that auctioning the right to play a public goods game with a provision point may have on equilibrium selection and individual behavior. Auctioning off such a right among a larger population of players strikingly enhances public good provision. Once public good provision is obtained, the auction price at the preliminary stage increases to its upper limit, dissipating all players' gains associated with the provision of the public good. Individual deviations from the equilibrium strategy are neither able to force lower market prices nor to affect provision of the public good in subsequent periods. (JEL C72, C92, H41)
A Graphical Exposition of the Economic Theory of Regulation
Authors: Beard T. Randolph , Kaserman David L. , Mayo John W.
Published: September 2003

This article provides a novel graphical exposition of the economic theory of regulation. In particular, we show—within a single graphical construct—a number of features that emerge from the theory. Through a variety of applications we are able to provide an improved understanding of many questions that have vexed economists, including the markets likely to be chosen for regulation, the propensity of regulatory benefits to be spread across interest groups, the symbiotic nature of regulation and cross‐subsidization, and the economics of deregulation. We also are able to depict graphically the relationship between the economic theory of regulation and the traditional normative model of regulation, which assumes that regulators maximize social welfare. (JEL D72, L51)
Expectations, Capital Gains, and Income
Authors: Hill Robert J. , Hill T. Peter
Published: September 2003

A theoretical framework for the measurement of income under uncertainty is developed that addresses some long‐standing controversies about the treatment of capital gains. The consequences for economic analysis and policy making are potentially serious, because the treatment of capital gains can significantly affect some major macroeconomic aggregates, including national income and savings, balance of payments deficits, government deficits, and depreciation. (JEL O47, P44, Q32)
The Intersection of Business, State Government, and Special Interests in Federal Legislation: An Examination of Congressional Votes on the Road to Interstate Branching
Authors: Colburn Christopher B. , Hudgins Sylvia C.
Published: September 2003

The approval of interstate branching in 1994 created a significant structural change in the banking industry. The influences captured by 1991 congressional votes resulting in a red light for interstate branching are examined using public choice variables, state banking law variables, and variables characterizing the business of banking by states. Our research offers a methodology for modeling voting behavior in the presences of intra‐industry conflicts and state versus federal government differences. We find that state and industry interests appear to influence votes more than political variables. (JEL G28, D72, L51)
Proxies in the New Political Economy: Caveat Emptor
Authors: Hanson John R.
Published: September 2003

Some common professional criteria for evaluating econometric tests that use proxies for political, social, and institutional variables as regressors may lull scholars into a false sense of security about specious results. The highly publicized correlations between income and economic freedom based on the economic freedom indexes supplied by the Fraser Institute, Heritage Foundation, and Freedom House are used as illustrations. Because these correlations bear strong resemblances to one another, most economists would consider them mutually supportive. Yet this is not so, implying that mutual resemblance and consistency are not criteria for judging econometric results. (JEL B49, C19)
Search and Taxation in a Model of Underground Economic Activities
Authors: Anderberg Dan , Balestrino Alessandro , Galmarini Umberto
Published: September 2003

We develop a simple model of an economy with underground production and trade. Because of the furtive nature of underground activities, information about trading opportunities in the irregular sector is less than perfect—hence, agents devote some time to locate trading partners in the black economy and then bargain over the terms of trade. The model stresses how individual involvement in underground economic activities is related to earnings capacity. It also highlights how taxes and tax enforcement are natural policy complements. Both results are argued to be useful when interpreting micro‐ and aggregate‐level data on underground economic activities. (JEL H26, H21, D72, D83)
Credible Commitments and Investment: Does Opportunistic Ability or Incentive Matter?
Authors: Falaschetti Dino
Published: September 2003

Private investment increases in a cross‐country panel when formal institutions (e.g., term limits) do not constrain executives' planning horizons. This evidence is consistent with institutions that encourage reputation‐building checking opportunistic incentives and extends evidence from domestic public choice applications to an international political economy setting. In addition, investment exhibits a nonmonotonic relationship with a polity's veto players. This relationship may reflect trade‐offs between constituents' monitoring‐capacity and agents' opportunistic ability. It may also highlight a channel through which lock‐in effects retard neoclassical convergence and thus motivate different normative prescriptions than those emerging from contributions where institutions and real activity must exhibit a monotonic relationship. (JEL D72, D78, E61)
Does Investment Risk Affect the Housing Decisions of Families?
Authors: Turner Tracy M.
Published: September 2003

Households assume substantial house‐price risk when purchasing a home. This article investigates the effect of such risk on families' housing decisions. Using a repeat cross‐section of household data from the American Housing Survey spanning a 10‐year period and measures of expected return and time‐varying risk, I find that families are less likely to own and housing demand is reduced during episodes of relatively high, anticipated house‐price volatility. The impact is greater on low‐ and moderate‐income families and first‐time homeowners than other groups. The results hold implications for policies designed to assist homeowners in lessening the risk they bear. (JEL R21, D12, D84)
On the Evolution of Competitive Balance: The Impact of an Increasing Global Search
Authors: Schmidt Martin B. , Berri David J.
Published: September 2003

The Coase theorem maintains that where free‐market precepts exist, the allocation of property rights does not impact the distribution of resources. An application to Major League Baseball suggests that institutions such as free agency and the reverse‐order amateur draft would not impact player distributions and therefore would not impact competitive balance. The present study finds that the distribution of wins is generally consistent with the precepts of the Coase theorem and therefore suggests a course for those who wish to alter the level of competitive balance: Major League Baseball should increase its focus on expanding the size of its labor pool. (JEL O15, L83, C22)
And a Hockey Game Broke Out: Crime and Punishment in the NHL
Authors: Heckelman Jac C. , Yates Andrew J.
Published: September 2003

We apply the economic theory of crime to the National Hockey League. We analyze a natural experiment in which games during the 1999–2000 season had either one or two referees. We determine the effect of the number of referees on both the number of penalties called and the number of rules infractions committed by players. The results indicate that increasing the number of referees leads to greater enforcement of the rules but does not significantly deter players from committing infractions. (JEL D0, K4)
GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity
Authors: Duprat Fabrice , Daw Michael , Lim Wonil , Collingridge Graham , Isaac John
Published: September 2003

AMPA-type glutamate receptors mediate most fast excitatory synaptic transmissions in the mammalian brain. They are critically involved in the expression of long-term potentiation and long-term depression, forms of synaptic plasticity that are thought to underlie learning and memory. A number of synaptic proteins have been identified that interact with the intracellular C-termini of AMPA receptor subunits. Here, we review recent studies and present new experimental data on the roles of these interacting proteins in regulating the AMPA receptor function during basal synaptic transmission and plasticity.
Kainate receptors and the induction of mossy fibre long-term potentiation
Authors: Bortolotto Zuner A. , Lauri Sari , Isaac John T. R. , Collingridge Graham L.
Published: September 2003

There is intense interest in understanding the molecular mechanisms involved in long-term potentiation (LTP) in the hippocampus. Significant progress in our understanding of LTP has followed from studies of glutamate receptors, of which there are four main subtypes (
α
-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA),
N
-methyl-D-aspartate (NMDA), mGlu and kainate). This article summarizes the evidence that the kainate subtype of glutamate receptor is an important trigger for the induction of LTP at mossy fibre synapses in the CA3 region of the hippocampus. The pharmacology of the first selective kainate receptor antagonists, in particular the GLU
K5
subunit selective antagonist LY382884, is described. LY382884 selectively blocks the induction of mossy fibre LTP, in response to a variety of different high-frequency stimulation protocols. This antagonist also inhibits the pronounced synaptic facilitation of mossy fibre transmission that occurs during high-frequency stimulation. These effects are attributed to the presence of presynaptic GLU
K5
-subunit-containing kainate receptors at mossy fibre synapses. Differences in kainate receptor-dependent synaptic facilitation of AMPA and NMDA receptor-mediated synaptic transmission are described. These data are discussed in the context of earlier reports that glutamate receptors are not involved in mossy fibre LTP and more recent experiments using kainate receptor knockout mice, that argue for the involvement of GLU
K6
but not GLU
K5
kainate receptor subunits. We conclude that activation of presynaptic GLU
K5
-containing kainate receptors is an important trigger for the induction of mossy fibre LTP in the hippocampus.
Imaging spatio-temporal patterns of long-term potentiation in mouse hippocampus
Authors: Hosokawa Toshiyuki , Ohta Masaki , Saito Takeshi , Fine Alan
Published: September 2003

Spatio-temporal patterns of neuronal activity before and after the induction of long-term potentiation in mouse hippocampal slices were studied using a real-time high-resolution optical recording system. After staining the slices with voltage-sensitive dye, transmitted light images and extracellular field potentials were recorded in response to stimuli applied to CA1 stratum radiatum. Optical and electrical signals in response to single test pulses were enhanced for at least 30 minutes after brief high-frequency stimulation at the same site. In two-pathway experiments, potentiation was restricted to the tetanized pathway. The optical signals demonstrated that both the amplitude and area of the synaptic response were increased, in patterns not predictable from the initial, pretetanus, pattern of activation. Optical signals will be useful for investigating spatio-temporal patterns of synaptic enhancement underlying information storage in the brain.
MAPK, CREB andzif268are all required for the consolidation of recognition memory
Authors: Bozon Bruno , Kelly Áine , Josselyn Sheena A. , Silva Alcino J. , Davis Sabrina , Laroche Serge
Published: September 2003

There has been nearly a century of interest in the idea that encoding and storage of information in the brain requires changes in the efficacy of synaptic connections between neurons that are activated during learning. Recent research into the molecular mechanisms of long-term potentiation (LTP) has brought about new knowledge that has provided valuable insights into the neural mechanisms of memory storage. The evidence indicates that rapid activation of the genetic machinery can be a key mechanism underlying the enduring modification of neural networks required for the stability of memories. In recent years, a wealth of experimental data has highlighted the importance of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling in the regulation of gene transcription in neurons. Here, we briefly review experiments that have shown MAPK/ERK, cAMP response element-binding protein (CREB) and the immediate early gene (IEG)zif268are essential components of a signalling cascade required for the expression of late phase LTP and of certain forms of long-term memory. We also present experiments in which we have assessed the role of these three molecules in recognition memory. We show that pharmacological blockade of MAPK/ERK phosphorylation, functional inactivation of CREB in an inducible transgenic mouse and inactivation ofzif268in a mutant mouse result in a similar deficit in long-term recognition memory. In the continuing debate about the role of LTP mechanisms in memory, these findings provide an important complement to the suggestion that synaptic changes brought about by LTP and memory consolidation and storage share, at least in part, common underlying molecular mechanisms.
The discovery of long-term potentiation
Authors: Lømo Terje
Published: September 2003

This paper describes circumstances around the discovery of long-term potentiation (LTP). In 1966, I had just begun independent work for the degree of
Dr medicinae
(PhD) in Per Andersen's laboratory in Oslo after an eighteen-month apprenticeship with him. Studying the effects of activating the perforant path to dentate granule cells in the hippocampus of anaesthetized rabbits, I observed that brief trains of stimuli resulted in increased efficiency of transmission at the perforant path-granule cell synapses that could last for hours. In 1968, Tim Bliss came to Per Andersen's laboratory to learn about the hippocampus and field potential recording for studies of possible memory mechanisms. The two of us then followed up my preliminary results from 1966 and did the experiments that resulted in a paper that is now properly considered to be the basic reference for the discovery of LTP.
Expression mechanisms underlying long-term potentiation: a postsynaptic view
Authors: Nicoll Roger A.
Published: September 2003

This review summarizes the various experiments that have been carried out to determine if the expression of long-term potentiation (LTP), in particularN-methyl-D-aspartate (NMDA) receptor-dependent LTP, is presynaptic or postsynaptic. Evidence for a presynaptic expression mechanism comes primarily from experiments reporting that glutamate overflow is increased during LTP and from experiments showing that the failure rate decreases during LTP. However, other experimental approaches, such as monitoring synaptic glutamate release by recording astrocytic glutamate transporter currents, have failed to detect any change in glutamate release during LTP. In addition, the discovery of silent synapses, in which LTP rapidly switches on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function at NMDA-receptor-only synapses, provides a postsynaptic mechanism for the decrease in failures during LTP. It is argued that the preponderance of evidence favours a postsynaptic expression mechanism, whereby NMDA receptor activation results in the rapid recruitment of AMPA receptors as well as a covalent modification of synaptic AMPA receptors.
Silent synapses: what are they telling us about long-term potentiation?
Authors: Kullmann Dimitri M.
Published: September 2003

At several cortical synapses glutamate release events can be mediated exclusively by NMDA receptors, with no detectable contribution from AMPA receptors. This observation was originally made by comparing the trial-to-trial variability of the two components of synaptic signals evoked in hippocampal neurons, and was subsequently confirmed by recording apparently pure NMDA receptor-mediated EPSCs with stimulation of small numbers of axons. It has come to be known as the ‘silent synapse’ phenomenon, and is widely assumed to be caused by the absence of functional AMPA receptors, which can, however, be recruited into the postsynaptic density by long-term potentiation (LTP) induction. Thus, it provides an important impetus for relating AMPA receptor trafficking mechanisms to the expression of LTP, a theme that is taken up elsewhere in this issue. This article draws attention to several findings that call for caution in identifying silent synapses exclusively with synapses without AMPA receptors. In addition, it attempts to identify several missing pieces of evidence that are required to show that unsilencing of such synapses is entirely accounted for by insertion of AMPA receptors into the postsynaptic density. Some aspects of the early stages of LTP expression remain open to alternative explanations.
Long-term potentiation, cooperativity and Hebb's cell assemblies: a personal history
Authors: McNaughton Bruce L.
Published: September 2003

The early history of the experimental work leading to the discovery that long-term potentiation (LTP) embodies Hebb's principle of association is described. In addition, the fallacy underlying the sometimes presumed distinction between ‘cooperativity’ and ‘associativity’ in the induction of LTP is pointed out.
A prelude to long-term potentiation
Authors: Andersen Per
Published: September 2003

Searching for premonitory studies of hippocampal long-term potentiation (LTP), there is a paucity of data. While synaptic enhancement during repetitive activation was studied in several reports from many groups between 1955 and 1967, the reported after-effects were short, at the most lasting a few minutes. Responses lasting for more than 1 hour were not reported until 1973.
AMPA receptor trafficking and long-term potentiation
Authors: Malinow Roberto
Published: September 2003

Activity-dependent changes in synaptic function are believed to underlie the formation of memories. A prominent example is long-term potentiation (LTP), whose mechanisms have been the subject of considerable scrutiny over the past few decades. I review studies from our laboratory that support a critical role for AMPA receptor trafficking in LTP and experience-dependent plasticity.
Synaptic plasticity in the mesolimbic dopamine system
Authors: Thomas Mark J. , Malenka Robert C.
Published: September 2003

Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that mediate all forms of experience-dependent plasticity. It has, however, been difficult to demonstrate directly that experience causes long-lasting changes in synaptic strength and that these mediate changes in behaviour. To address these potential functional roles of LTP and LTD, we have taken advantage of the powerful
in vivo
effects of drugs of abuse that exert their behavioural effects in large part by acting in the nucleus accumbens (NAc) and ventral tegmental area (VTA); the two major components of the mesolimbic dopamine system. Our studies suggest that
in vivo
drugs of abuse such as cocaine cause long-lasting changes at excitatory synapses in the NAc and VTA owing to activation of the mechanisms that underlie LTP and LTD in these structures. Thus, administration of drugs of abuse provides a distinctive model for further investigating the mechanisms and functions of synaptic plasticity in brain regions that play important roles in the control of motivated behaviour, and one with considerable practical implications.
The induction of
N
-methyl-D-aspartate receptor-dependent long-term potentiation
Authors: Collingridge Graham L.
Published: September 2003

The role of
N
-methyl-D-aspartate (NMDA) receptors in the induction of long-term potentiation (LTP) was established during the 1980s. In this article I present a personal reflection upon the role that my colleagues and I played in the discovery of the mechanism of induction of NMDA receptor-dependent LTP.
Genetic neuroscience of mammalian learning and memory
Authors: Tonegawa Susumu , Nakazawa Kazu , Wilson Matthew A.
Published: September 2003

Our primary research interest is to understand the molecular and cellular mechanisms on neuronal circuitry underlying the acquisition, consolidation and retrieval of hippocampus-dependent memory in rodents. We study these problems by producing genetically engineered (i.e. spatially targeted and/or temporally restricted) mice and analysing these mice by multifaceted methods including molecular and cellular biology,
in vitro
and
in vivo
physiology and behavioural studies. We attempt to identify deficits at each of the multiple levels of complexity in specific brain areas or cell types and deduce those deficits that underlie specific learning or memory. We will review our recent studies on the acquisition, consolidation and recall of memories that have been conducted with mouse strains in which genetic manipulations were targeted to specific types of cells in the hippocampus or forebrain of young adult mice.
Inducible molecular switches for the study of long-term potentiation
Authors: Hédou Gaël , Mansuy Isabelle M.
Published: September 2003

This article reviews technical and conceptual advances in unravelling the molecular bases of long-term potentiation (LTP), learning and memory using genetic approaches. We focus on studies aimed at testing a model suggesting that protein kinases and protein phosphatases balance each other to control synaptic strength and plasticity. We describe how gene ‘knock-out’ technology was initially exploited to disrupt the Ca2+/calmodulin-dependent protein kinase IIα(CaMKIIα) gene and how refined knock-in techniques later allowed an analysis of the role of distinct phosphorylation sites in CaMKII. Further to gene recombination, regulated gene expression using the tetracycline-controlled transactivator and reverse tetracycline-controlled transactivator systems, a powerful new means for modulating the activity of specific molecules, has been applied to CaMKIIαand the opposing protein phosphatase calcineurin. Together with electro-physiological and behavioural evaluation of the engineered mutant animals, these genetic methodologies have helped gain insight into the molecular mechanisms of plasticity and memory. Further technical developments are, however, awaited for an even higher level of finesse.
In search of general mechanisms for long-lasting plasticity:Aplysiaand the hippocampus
Authors: Pittenger Christopher , Kandel Eric R.
Published: September 2003

Long-term synaptic plasticity is thought to underlie many forms of long-lasting memory. Long-lasting plasticity has been most extensively studied in the marine snailAplysiaand in the mammalian hippocampus, where Bliss and Lømo first described long-term potentiation 30 years ago. The molecular mechanisms of plasticity in these two systems have proven to have many similarities. Here, we briefly describe some of these areas of overlap. We then summarize recent advances in our understanding of the mechanisms of long-lasting synaptic facilitation inAplysiaand suggest that these may prove fruitful areas for future investigation in the mammalian hippocampus and at other synapses in the mammalian brain.
Active dendrites, potassium channels and synaptic plasticity
Authors: Johnston Daniel , Christie Brian R. , Frick Andreas , Gray Richard , Hoffman Dax A. , Schexnayder Lalania K. , Watanabe Shigeo , Yuan Li-Lian
Published: September 2003

The dendrites of CA1 pyramidal neurons in the hippocampus express numerous types of voltage-gated ion channel, but the distributions or densities of many of these channels are very non-uniform. Sodium channels in the dendrites are responsible for action potential (AP) propagation from the axon into the dendrites (back-propagation); calcium channels are responsible for local changes in dendritic calcium concentrations following back-propagating APs and synaptic potentials; and potassium channels help regulate overall dendritic excitability. Several lines of evidence are presented here to suggest that back-propagating APs, when coincident with excitatory synaptic input, can lead to the induction of either long-term depression (LTD) or long-term potentiation (LTP). The induction of LTD or LTP is correlated with the magnitude of the rise in intracellular calcium. When brief bursts of synaptic potentials are paired with postsynaptic APs in a theta-burst pairing paradigm, the induction of LTP is dependent on the invasion of the AP into the dendritic tree. The amplitude of the AP in the dendrites is dependent, in part, on the activity of a transient, A-type potassium channel that is expressed at high density in the dendrites and correlates with the induction of the LTP. Furthermore, during the expression phase of the LTP, there are local changes in dendritic excitability that may result from modulation of the functioning of this transient potassium channel. The results support the view that the active properties of dendrites play important roles in synaptic integration and synaptic plasticity of these neurons.
Fusion pore modulation as a presynaptic mechanism contributing to expression of long-term potentiation
Authors: Choi Sukwoo , Klingauf Jürgen , Tsien Richard W.
Published: September 2003

Working on the idea that postsynaptic and presynaptic mechanisms of long-term potentiation (LTP) expression are not inherently mutually exclusive, we have looked for the existence and functionality of presynaptic mechanisms for augmenting transmitter release in hippocampal slices. Specifically, we asked if changes in glutamate release might contribute to the conversion of ‘silent synapses’ that show
N
-methyl-D-aspartate (NMDA) responses but no detectable
α
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) responses, to ones that exhibit both. Here, we review experiments where NMDA receptor responses provided a bioassay of cleft glutamate concentration, using opposition between peak [glu]
cleft
and a rapidly reversible antagonist, L-AP5. We discuss findings of a dramatic increase in peak [glu]
cleft
upon expression of pairing-induced LTP (Choi). We present simulations with a quantitative model of glutamatergic synaptic transmission that includes modulation of the presynaptic fusion pore, realistic cleft geometry and a distributed array of postsynaptic receptors and glutamate transporters. The modelling supports the idea that changes in the dynamics of glutamate release can contribute to synaptic unsilencing. We review direct evidence from Renger
et al
., in accord with the modelling, that trading off the strength and duration of the glutamate transient can markedly alter AMPA receptor responses with little effect on NMDA receptor responses. An array of additional findings relevant to fusion pore modulation and its proposed contribution to LTP expression are considered.
Long-term potentiation in the dentate gyrus of the anaesthetized rat is accompanied by an increase in extracellular glutamate: real-time measurements using a novel dialysis electrode
Authors: Errington M. L. , Galley P. T. , Bliss T. V. P.
Published: September 2003

We have used a glutamate-specific dialysis electrode to obtain real-time measurements of changes in the concentration of glutamate in the extracellular space of the hippocampus during low-frequency stimulation and following the induction of long-term potentiation (LTP). In the dentate gyrus, stimulation of the perforant path at 2 Hz for 2 min produced a transient increase in glutamate current relative to the basal value at control rates of stimulation (0.033 Hz). This activity-dependent glutamate current was significantly enhanced 35 and 90 min after the induction of LTP. The maximal 2 Hz signal was obtained during post-tetanic potentiation (PTP). There was also a more gradual increase in the basal level of extracellular glutamate following the induction of LTP. Both the basal and activity-dependent increases in glutamate current induced by tetanic stimulation were blocked by local infusion of the
N
-methyl-D-aspartate receptor antagonist D-APV. In areas CA1 and CA3 we were unable to detect a 2 Hz glutamate signal either before or after the induction of LTP, possibly owing to a more avid uptake of glutamate in the pyramidal cell fields. These results demonstrate that LTP in the dentate gyrus is associated with a greater concentration of extracellular glutamate following activation of potentiated synapses, either because potentiated synapses release more transmitter per impulse, or because of reduced uptake by glutamate transporters. We present arguments favouring increased release rather than decreased uptake.
Bidirectional synaptic plasticity: from theory to reality
Authors: Bear Mark F.
Published: September 2003

Theories of receptive field plasticity and information storage make specific assumptions for how synapses are modified. I give a personal account of how testing the validity of these assumptions eventually led to a detailed understanding of long-term depression and metaplasticity in hippocampal area CA1 and the visual cortex. The knowledge of these molecular mechanisms now promises to reveal when and how sensory experience modifies synapses in the cerebral cortex.
Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory
Authors: Morris R. G. M. , Moser E. I. , Riedel G. , Martin S. J. , Sandin J. , Day M. , O'Carroll C.
Published: September 2003

The hypothesis that synaptic plasticity is a critical component of the neural mechanisms underlying learning and memory is now widely accepted. In this article, we begin by outlining four criteria for evaluating the ‘synaptic plasticity and memory (SPM)’ hypothesis. We then attempt to lay the foundations for a specific neurobiological theory of hippocampal (HPC) function in which activity-dependent synaptic plasticity, such as long-term potentiation (LTP), plays a key part in the forms of memory mediated by this brain structure. HPC memory can, like other forms of memory, be divided into four processes: encoding, storage, consolidation and retrieval. We argue that synaptic plasticity is critical for the encoding and intermediate storage of memory traces that are automatically recorded in the hippocampus. These traces decay, but are sometimes retained by a process of cellular consolidation. However, we also argue that HPC synaptic plasticity is not involved in memory retrieval, and is unlikely to be involved in systems-level consolidation that depends on HPC-neocortical interactions, although neocortical synaptic plasticity does play a part. The information that has emerged from the worldwide focus on the mechanisms of induction and expression of plasticity at individual synapses has been very valuable in functional studies. Progress towards a comprehensive understanding of memory processing will also depend on the analysis of these synaptic changes within the context of a wider range of systems-level and cellular mechanisms of neuronal transmission and plasticity.
The fate and function of glycosphingolipid glucosylceramide
Authors: van Meer Gerrit , Wolthoorn Jasja , Degroote Sophie
Published: September 2003

In higher eukaryotes, glucosylceramide is the simplest member and precursor of a fascinating class of membrane lipids, the glycosphingolipids. These lipids display an astounding variation in their carbohydrate head groups, suggesting that glycosphingolipids serve specialized functions in recognition processes. It is now realized that they are organized in signalling domains on the cell surface. They are of vital importance as, in their absence, embryonal development is inhibited at an early stage. Remarkably, individual cells can live without glycolipids, perhaps because their survival does not depend on glycosphingolipid–mediated signalling mechanisms. Still, these cells suffer from defects in intracellular membrane transport. Various membrane proteins do not reach their intracellular destination, and, indeed, some intracellular organelles do not properly differentiate to their mature stage. The fact that glycosphingolipids are required for cellular differentiation suggests that there are human diseases resulting from defects in glycosphingolipid synthesis. In addition, the same cellular differentiation processes may be affected by defects in the degradation of glycosphingolipids. At the cellular level, the pathology of glycosphingolipid storage diseases is not completely understood. Cell biological studies on the intracellular fate and function of glycosphingolipids may open new ways to understand and defeat not only lipid storage diseases, but perhaps other diseases that have not been connected to glycosphingolipids so far.
Generation of CD1 tetramers as a tool to monitor glycolipid–specific T cells
Authors: Gadola Stephan D. , Karadimitris Anastasios , Zaccai Nathan R. , Salio Mariolina , Dulphy Nicolas , Shepherd Dawn , Yvonne Jones E. , Cerundolo Vincenzo
Published: September 2003

CD1 molecules are β2m–associated HLA class–I–like glycoproteins which have the unique ability to present glycolipid and phospholipid antigens to specific T lymphocytes. To study the biology of CD1 and its role in human disease we developed novel techniques for generation of recombinant CD1/lipid complexes by in vitro refolding. Fluorescent tetrameric complexes made from soluble recombinant CD1d/α–galactosylceramide complexes allowed highly sensitive and specificex vivoandin vitrodetection and functional characterization of novel human T–lymphocyte populations. Furthermore, protein crystals were obtained from soluble recombinant CD1b/β2m–proteins loaded either with phosphatidylinositol or ganglioside GM2, which led to the first atomic structure determination of a CD1/lipid complex. The analysis of these crystal structures clarified how CD1b molecules can bind lipid ligands of different size, and revealed a broader spectrum of potential CD1b ligands than previously predicted.
Glycosphingolipid functions: insights from engineered mouse models
Authors: Proia Richard L.
Published: September 2003

Glycosphingolipids are remarkable for their structural complexity and their distinctive patterns that mark different tissues and stages of development. The physiological functions of glycosphingolipids are likely to be profound and are only beginning to emerge. Much of this new information is due to the study of mutant mice lacking specific sets of glycosphingolipids, the topic of this review.
Enzyme replacement therapy: conception, chaos and culmination
Authors: Brady Roscoe O.
Published: September 2003

Soon after the enzymatic defects in Gaucher disease and in Niemann–Pick disease were discovered, enzyme replacement or enzyme supplementation was proposed as specific treatment for patients with these and related metabolic storage disorders. While relatively straightforward in concept, successful implementation of this approach required many years of intensive effort to bring it to fruition. Procedures were eventually developed to produce sufficient quantities of the requisite enzymes for clinical trials and to target therapeutic enzymes to lipid–storing cells. These achievements led to the development of effective enzyme replacement therapy for patients with Gaucher disease and for Fabry disease. These demonstrations provide strong incentive for the application of this strategy for the treatment of many human disorders of metabolism.
Future perspectives for glycolipid research in medicine
Authors: Cox Timothy M.
Published: September 2003

Medical interest in glycolipids has been mainly directed to the rare and complex glycosphingolipid storage disorders that are principally caused by unitary deficiencies of lysosomal acid hydrolases. However, glycolipids are critical components of cell membranes and occur within newly described membrane domains known as lipid rafts. Glycolipids are components of important antigen systems and membrane receptors; they participate in intracellular signalling mechanisms and may be presented to the immune system in the context of the novel CD1 molecules present on T lymphocytes. A knowledge of their mechanism of action in the control of cell growth and survival as well as developmental pathways is likely to shed light on the pathogenesis of the glycosphingolipid storage disorders as well as the role of lipid second messengers in controlling cell mobility and in the mobilization of intracellular calcium stores (a biological role widely postulated particularly for the lysosphingolipid metabolite sphingosine 1–phosphate). Other sphingolipid metabolites such as ceramide 1–phosphate may be involved in apoptotic responses and in phagocytosis and synaptic vesicle formation. The extraordinary pharmaceutical success of enzymatic complementation for Gaucher's disease using macrophage–targeted human glucocerebrosidase has focused further commercial interest in other glycolipid storage diseases: the cost of targeted enzyme therapy and its failure to restore lysosomal enzymatic deficiencies in the brain has also stimulated interest in the concept of substrate reduction therapy using diffusible inhibitory molecules. Successful clinical trials of the iminosugar
N
–butyldeoxynojirimycin in type 1 Gaucher's disease prove the principle of substrate reduction therapy and have attracted attention to this therapeutic method. They will also foster important further experiments into the use of glycolipid synthesis inhibitors for the severe neuronopathic glycosphingolipidoses, for which no definitive treatment is otherwise available. Future glycolipid research in medicine will be directed to experiments that shed light on the role of sphingolipids in signalling pathways, and in the comprehensive characterization and their secretory products in relation to the molecular pathogenesis of the storage disorders; experiments of use to improve the efficiency of complementing enzymatic delivery to the lysosomal compartment of storage cells are also needed. Further systematic screening for inhibitory compounds with specific actions in the pathways of glycosphingolipid biosynthesis will undoubtedly lead to clinical trials in the neuronopathic storage disorders and to wider applications in the fields of immunity and cancer biology.
Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease
Authors: Moyses Chris
Published: September 2003

Glycosphingolipid (GSL) lysosomal storage disorders are inherited enzyme deficiencies that result in pathological lysosomal accumulation of glycolipids, with widespread clinical consequences. Type 1 Gaucher disease is the commonest of these; the deficient enzyme in this condition is glucocerebrosidase. Clinical manifestations include hepatosplenomegaly, thrombocytopenia, anaemia, recurrent infections and skeletal lesions. The condition can be treated with intravenous enzyme replacement therapy (ERT). Substrate reduction therapy is a new approach in which glycolipid accumulation is counteracted not by replacing the deficient enzyme but by reducing the substrate level to better balance residual activity of the deficient enzyme. Miglustat is an inhibitor of glucosylceramide synthase, a key enzyme in GSL synthesis. Oral administration of miglustat to patients with type 1 Gaucher disease attenuates the synthesis of glucocerebroside, the substrate of the deficient glucocerebrosidase. In the first clinical study, patients with type 1 Gaucher disease who had enlargement of the liver or spleen and (if present) the spleen at baseline received 12 months treatment with oral miglustat. There were mean decreases in liver and spleen volumes of 12% (7.9–16.4,
p
< 0.001) and 19% (14.3–23.7,
p
< 0.001), respectively. Mean haemoglobin increased by 0.26 g dl
−1
(−0.5−0.57, not statistically significant) and platelet count by 8.3 × 10
9
l
−1
(1.9–14.7,
p
= 0.014).
Gaucher disease and the clinical experience with substrate reduction therapy
Authors: Zimran Ari , Elstein Deborah
Published: September 2003

Gaucher disease is caused by an enzymatic defect with consequent accumulation of glucocerebroside. Type I, the non–neuronopathic form, is rather common and panethnic. Patients may present with hepatosplenomegaly, anaemia, thrombocytopenia and skeletal or lung involvement. Enzyme replacement therapy ameliorates disease symptoms and signs; however, it involves lifelong intravenous therapy, is costly and is incapable of crossing the blood–brain barrier. Substrate reduction with
N
–butyldeoxynojirimycin (OGT 918) is a harbinger of oral iminosugars for glycolipid storage disorders. Long–term data in the seminal trial (100 mg three times per day), demonstrate safety and efficacy in adult type I patients naive to enzyme therapy, and suggest its application in patients unwilling or unable to receive enzyme replacement and tolerating side effects, including diarrhoea, weight loss, tremor and peripheral neuropathy (mostly reversible with dose reduction or withdrawal). Dose dependency was demonstrated with 50 mg three times per day. In patients stabilized on enzyme therapy switched from or in combination with enzyme, no deterioration in disease parameters was seen but side effects were as above. Although efficacy is less dramatic than enzyme treatment, it may be that plateaux are achieved asymptotically so therapeutic outcomes with OGT 918 may ultimately be comparable. Yet, given the above side effects and the lack of long–term experience, patients with very mild manifestations would probably not be appropriate candidates.
Biochemistry of glycosphingolipid storage disorders: implications for therapeutic intervention
Authors: Aerts Johannes M. , Hollak Carla , Boot Rolf , Groener Ans
Published: September 2003

The physiological importance of the degradative processes in lysosomes is revealed by the existence of at least 40 distinct inherited diseases, the so–called lysosomal storage disorders. Most of these diseases are caused by a deficiency in a single lysosomal enzyme, or essential cofactor, and result in the lysosomal accumulation of one, or sometimes several, natural compounds. The most prevalent subgroup of the lysosomal storage disorders is formed by the sphingolipidoses, inherited disorders that are characterized by excessive accumulation of one or multiple (glyco)sphingolipids. The biology of glycosphingolipids has been extensively discussed in other contributions during this symposium. This review will therefore focus in depth on (type 1) Gaucher disease, a prototypical glycosphingolipidosis. The elucidation of the primary genetic defect, being a deficiency in the lysosomal glucocerebrosidase, is described. Characterization of glucocerebrosidase at protein and gene level has subsequently opened avenues for therapeutic intervention. The development of successful enzyme replacement therapy for type 1 Gaucher disease is discussed. Attention is also paid to the alternative approach of substrate modulation using orally administered inhibitors of glucosylceramide synthesis. Novel developments about the monitoring of age of onset, progression and correction of disease are described. The remaining challenges about pathophysiology of glycosphingolipidoses are discussed in view of further improvements in therapy for these debilitating disorders.
Formation of functional cell membrane domains: the interplay of lipid– and protein–mediated interactions
Authors: Harder Thomas
Published: September 2003

Numerous cell membrane associated processes, including signal transduction, membrane sorting, protein processing and virus trafficking take place in membrane subdomains. Protein–protein interactions provide the frameworks necessary to generate biologically functional membrane domains. For example, coat proteins define membrane areas destined for sorting processes, viral proteins self–assemble to generate a budding virus, and adapter molecules organize multimolecular signalling assemblies, which catalyse downstream reactions. The concept of raft lipid–based membrane domains provides a different principle for compartmentalization and segregation of membrane constituents. Accordingly, rafts are defined by the physical properties of the lipid bilayer and function by selective partitioning of membrane lipids and proteins into membrane domains of specific phase behaviour and lipid packing. Here, I will discuss the interplay of these independent principles of protein scaffolds and raft lipid microdomains leading to the generation of biologically functional membrane domains.
Endocytic trafficking of glycosphingolipids in sphingolipid storage diseases
Authors: Pagano Richard E.
Published: September 2003

In this review, recent studies of membrane lipid transport in sphingolipid (SL) storage disease (SLSD) fibroblasts are summarized. Several fluorescent glycosphingolipid (GSL) analogues are internalized from the plasma membrane via caveolae and are subsequently transported to the Golgi complex of normal fibroblasts, while in 10 different SLSD cell types, these lipids accumulate in endosomes and lysosomes. Additional studies have shown that cholesterol homeostasis is perturbed in multiple SLSDs secondary to accumulation of endogenous SLs, and that mis–targeting of the GSLs is regulated by cellular cholesterol. Golgi targeting of GSLs internalized via caveolae is dependent on microtubules and phosphoinositide 3–kinase(s) and is inhibited by expression of dominant–negative rab7 and rab9 constructs. Overexpression of wild–type rab7 or rab9 (but not rab11) in Niemann–Pick C fibroblasts results in correction of lipid trafficking defects, including restoration of Golgi targeting of fluorescent lactosylceramide and endogenous GM1 ganglioside (monitored by the transport of fluorescent cholera toxin), and a dramatic reduction in accumulation of intracellular cholesterol. These results suggest an approach for restoring normal lipid trafficking in this, and perhaps other, SLSD cell types, and may provide a basis for future therapy of these diseases.
Neurobiology and cellular pathogenesis of glycolipid storage diseases
Authors: Walkley Steven U.
Published: September 2003

Disorders of lysosomal metabolism often involve the accumulation of specific types of glycolipid, particularly gangliosides, because of either degradative failure or other currently unknown mechanisms. Although the precise role of gangliosides in cells remains enigmatic, the presence of specific abnormalities secondary to ganglioside accumulation in lysosomal diseases has suggested important biological functions. Chief among these is the growth of new dendrites on particular classes of mature neurons secondary to an increase in GM2 ganglioside. That GM2 has also been shown to be elevated in normal immature neurons coincident with dendritic sprouting provides a compelling argument that this ganglioside plays a role in dendritic initiation. This discovery has led to the search for other regulators of dendritic differentiation that may in some way be linked to the expression and/or function of GM2 ganglioside. Principal candidates that have emerged include tyrosine kinase receptors, small GTPases and calcium/calmodulin–dependent protein kinase II. Understanding the mechanism underlying ectopic dendritogenesis in lysosomal diseases can be expected to generate significant insight into the control of dendritic plasticity in normal brain. The detrimental aspects of ganglioside accumulation in storage diseases as well as the potential link between gangliosides and dendritogenesis also provide a strong rationale for developing pharmacological means to manipulate ganglioside expression in neurons.