Bidirectional synaptic plasticity: from theory to reality

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.     

Self-influencing synaptic plasticity: Recurrent changes of synaptic weights can lead to specific functional properties

Recent experimental results suggest that dendritic and back-propagating spikes can influence synaptic plasticity in different ways (Holthoff, 2004; Holthoff et al., 2005). In this study we investigate how these signals could interact at dendrites in space and time leading to changing plasticity properties at local synapse clusters. Similar to a previous study (Saudargiene et al., 2004) we employ a differential Hebbian learning rule to emulate spike-timing dependent plasticity and investigate how the interaction of dendritic and back-propagating spikes, as the post-synaptic signals, could influence plasticity. Specifically, we will show that local synaptic plasticity driven by spatially confined dendritic spikes can lead to the emergence of synaptic clusters with different properties. If one of these clusters can drive the neuron into spiking, plasticity may change and the now arising global influence of a back-propagating spike can lead to a further segregation of the clusters and possibly the dying-off of some of them leading to more functional specificity. These results suggest that through plasticity being a spatial and temporal local process, the computational properties of dendrites or complete neurons can be substantially augmented. Action Editor: Wulfram Gerstner     

From synaptic spines to nuclear signaling: nuclear and synaptic actions of the amyloid precursor protein

Despite intensive studies of the secretase‐mediated processing of the amyloid precursor protein (APP) to form the amyloid β‐peptide (Aβ), in relation to Alzheimer's disease (AD), no new therapeutic agents have reached the clinics based on reducing Aβ levels through the use of secretase inhibitors or immunotherapy. Furthermore, the normal neuronal functions of APP and its various metabolites still remain under‐investigated and unclear. Here, we highlight emerging areas of APP function that may provide new insights into synaptic development, cognition, and gene regulation. By modulating expression levels of endogenous APP in primary cortical neurons, the frequency and amplitude of calcium oscillations is modified, implying a key role for APP in maintaining neuronal calcium homeostasis essential for synaptic transmission. Disruption of this homeostatic mechanism predisposes to aging and AD. Synaptic spine loss is a feature of neurogeneration resulting in learning and memory deficits, and emerging evidence indicates a role for APP, probably mediated via one or more of its metabolites, in spine structure and functions. The intracellular domain of APP (AICD) has also emerged as a key epigenetic regulator of gene expression controlling a diverse range of genes, including APP itself, the amyloid‐degrading enzyme neprilysin, and aquaporin‐1. A fuller understanding of the physiological and pathological actions of APP and its metabolic network could provide new opportunities for therapeutic intervention in AD.     

Redistribution of synaptic efficacy: A mechanism to generate infinite synaptic input diversity from a homogenous population of neurons without changing absolute synaptic efficacies

Changing the reliability of neurotransmitter release results in a change in the efficay of low frequency synaptic transmission and in the rate of high frequency synaptic depression thus it can not cause an uniform change in strength of synapses and instead results in a change in the dynamics of synaptic transmission referred to as ‘redistribution of synaptic efficacy’ (RSE). Since the change in synaptic transmission associated with RSE depends on the history of action potential activity it is concluded that RSE serves as a mechanism to generate a potentially infinite diversity of synaptic input.     

Glutamate uptake in synaptic plasticity: from mollusc to mammal

A great deal of research has been directed toward understanding the cellular mechanisms underlying synaptic plasticity and memory formation. To this point, most research has focused on the more "active" components of synaptic transmission: presynaptic transmitter release and postsynaptic transmitter receptors. Little work has been done characterizing the role neurotransmitter transporters might play during changes in synaptic efficacy. We review several new experiments that demonstrate glutamate transporters are regulated during changes in the efficacy of glutamatergic synapses. This regulation occurred during long-term facilitation of the sensorimotor synapse of Aplysia and long-term potentiation of the Schaffer-collateral synapse of the rat. We propose that glutamate transporters are "co-regulated" with other molecules/processes involved in synaptic plasticity, and that this process is phylogenetically conserved. These new findings indicate that glutamate transporters most likely play a more active role in neurotransmission than previously believed.     

Homeostatic synaptic plasticity: from single synapses to neural circuits

Homeostatic synaptic plasticity remains an enigmatic form of synaptic plasticity. Increasing interest on the topic has fuelled a surge of recent studies that have identified key molecular players and the signaling pathways involved. However, the new findings also highlight our lack of knowledge concerning some of the basic properties of homeostatic synaptic plasticity. In this review we address how homeostatic mechanisms balance synaptic strengths between the presynaptic and the postsynaptic terminals and across synapses that share the same postsynaptic neuron.     

Dynamical synaptic plasticity: a model and connection to some experiments

 Using a modified version of a phenomenological model for the dynamics of synaptic plasticity, we examine some recent experiments of Wu et al. [(2001) J Physiol 533:745–755]. We show that the model is quantitatively consistent with their experimental protocols producing long-term potentiation (LTP) and long-term depression (LTD) in slice preparations of rat hippocampus. We also predict the outcome of similar experiments using different frequencies and depolarization levels than reported in their results. Received: 3 September 2002 / Accepted in revised form: 22 October 2002 / Published online: 24 February 2003 Correspondence to: H.D.I. Abarbanel (e-mail: hdia@jacobi.ucsd.edu) Acknowledgements. We are very grateful to A. Selverston and D. Feldman for conversations about this work. This work was partially supported by the U.S. Department of Energy, Office of Basic Energy Sciences, Division of Engineering and Geosciences, under grants No. DE-FG03-90ER14138 and No. DE-FG03-96ER14592, by a grant from the National Science Foundation, NSF PHY0097134, by a grant from the Army Research Office, DAAD19-01-1-0026, by a grant from the Office of Naval Research, N00014-00-1-0181, and by a grant from the National Institutes of Health, NIH R01 NS40110-01A2. This work was also partially supported by M. Ciencia y Tecnologa BFI2000-0157 (R.H.).     

Mechanisms of synaptic plasticity: from membrane to intracellular AMPAR trafficking

Brief periods of repetitive neural firing onto adjacent neurons can lead to changes in synaptic plasticity, that is, changes in the make-up of macromolecular complexes located at synapses. This process includes the regulated trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) to synaptic membranes. Little is known, however, about how the AMPARs are regulated before they are shuttled to the membrane. Greger et al. have found that the length of the cytoplasmic tails of constituent subunits of a given AMPAR is determined by editing [at a glutamine (Q) or an arginine (R) codon] near their C termini. Tail length, in turn, dictates whether AMPARs will be retained or quickly released from the endoplasmic reticulum.     

Advanced tracer techniques to monitor synaptic activity

The two approaches presented here bypass postsynaptic receptors as indicators of quantal release, and thus they can provide information which is clearly distinct from that obtained with standard electrophysiological techniques. Indeed, the inherently variable responsiveness of the postsynaptic membrane makes it an unreliable indicator of presynaptic activity and this has fueled a lot of controversy, particularly in the area of synaptic plasticity. A major advantage of these two methods is their ability to detect changes at the single bouton level. This offers a lot of advantages including the possibility to study the functional role for exo-endocytosis but also plasticity against a background of great variability among a large number of synapses. The spatial resolving power of FM1-43 and anti-synaptotagmin antibodies may be valuable in future studies of spread of LTP between neighboring synapses and in the mapping the pattern of neuronal activity in complex networks of neurons.     

Adaptation to synaptic inactivity in hippocampal neurons

In response to activity deprivation, CNS neurons undergo slow adaptive modification of unitary synaptic transmission. The changes are comparable in degree to those induced by brief intense stimulation, but their molecular basis is largely unknown. Our data indicate that prolonged AMPAR blockade acts through loss of Ca2+ entry through L-type Ca2+ channels to bring about an increase in both vesicle pool size and turnover rate, as well as a postsynaptic enhancement of the contribution of GluR1 homomers, concentrated at the largest synapses. The changes were consistent with a morphological scaling of overall synapse size, but also featured a dramatic shift toward synaptic drive contributed by the Ca2+-permeable homomeric GluR1 receptors. These results extend beyond "synaptic homeostasis" to involve more profound changes that can be better described as "metaplasticity".     

Sodium-independent taurine binding to brain synaptic membranes

Saturable sodium-independent taurine binding to mouse and rat brain synaptic membranes was exposed after two freezing-thawing cycles combined with Triton X-100 treatments. The amount of saturable taurine binding was fairly low but was enhanced after depletion of brain taurine. Saturable taurine binding was displaceable by some convulsants and anticonvulsants but is specificity still remains to be established.     

Getting to synaptic complexes through systems biology

Large numbers of synaptic components have been identified, but the effect so far on our understanding of synaptic function is limited. Now, network maps and annotated functions of individual components have been used in a systems biology approach to analyzing the function of NMDA receptor complexes at synapses, identifying biologically relevant modular networks within the complex.     

To think or not to think: synaptic activity and Abeta release

Accumulation of beta-amyloid protein (Abeta) in the extracellular space of the brain has been hypothesized to be a culprit in the pathogenesis of Alzheimer's disease. In this issue of Neuron, Cirrito et al. describe a series of experiments demonstrating that extracellular Abeta levels are directly modulated by neuronal and synaptic activity.