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PubMed2003

Elements of a neurobiological theory of the hippocampus: the role of activity-dependent synaptic plasticity in memory.

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.

Animals↗
PubMed2006

Partial inhibition of PP1 alters bidirectional synaptic plasticity in the hippocampus.

Synaptic plasticity is an important cellular mechanism that underlies memory formation. In brain areas involved in memory such as the hippocampus, long-term synaptic plasticity is bidirectional. Major forms of bidirectional plasticity encompass long-term potentiation (LTP), LTP reversal (depotentiation) and long-term depression (LTD). Protein kinases and protein phosphatases are important players in the induction of both LTP and LTD, and the serine/threonine protein phosphatase-1 (PP1), in particular, has emerged as a key phosphatase in these processes. The goal of the present study was to assess the contribution of PP1 to bidirectional plasticity and examine the impact of a partial inhibition of PP1 on LTP, LTD and depotentiation in the mouse hippocampus. For this, we used transgenic mice expressing an active PP1 inhibitor (I-1*) inducibly in forebrain neurons. We show that partial inhibition of PP1 by I-1* expression alters the properties of bidirectional plasticity by inducing a shift of synaptic responses towards potentiation. At low-frequency stimulation, PP1 inhibition decreases LTD in a frequency-dependent fashion. It favours potentiation over depression at intermediate frequencies and increases LTP at high frequency. Consistently, it also impairs depotentiation. These results indicate that the requirement of bidirectional plasticity for PP1 is frequency-dependent and that a broad range of plasticity is negatively constrained by PP1, a feature that may correlate with the property of PP1 to constrain learning efficacy and promote forgetting.

Action Potentials↗
PubMed2006

Glial cells in synaptic plasticity.

Plasticity of synaptic transmission is believed to be the cellular basis for learning and memory, and depends upon different pre- and post-synaptic neuronal mechanisms. Recently, however, an increasing number of studies have implicated a third element in plasticity; the perisynaptic glial cell. Originally glial cells were thought to be important for metabolic maintenance and support of the nervous system. However, work in the past decade has clearly demonstrated active involvement of glia in stability and overall nervous system function as well as synaptic plasticity. Through specific modulation of glial cell function, a wide variety of roles for glia in synaptic plasticity have been uncovered. Furthermore, interesting circumstantial evidence suggests a glial involvement in multiple other types of plasticity. We will discuss recent advances in neuron-glial interactions that take place during synaptic plasticity and explore different plasticity phenomena in which glial cells may be involved.

Animals↗
PubMed2003

[Changes in long-term synaptic plasticity in the spinal dorsal horn of neuropathic pain rats].

OBJECTIVE: To observe the change in induction of long-term potentiation (LTP) of C-fiberevoked potentials in the spinal dorsal horn of neuropathic pain rats, examine the changes in plasticity of synaptic transmission, and explore the effects and mechanisms of central sensitization and neuropathic pain following noxious stimulation or nerve injury. METHODS: Neuropathic pain model was produced by tight ligation of the L5/L6 spinal nerve in Sprague-Dawley rats and the control group rats were received sham operation. The C-fiber-evoked field potentials in rat spinal dorsal horn were recorded by extracellular recording techniques. The differences in induction of LTP of C-fiber dorsal horn field potentials in sham-operated and neuropathic pain rats were compared. RESULTS: (1) In neuropathic pain rats, the LTP in the dorsal horn was induced by high-frequency, low-intensity conditioning stimulation (100 Hz, 10 V, 0.5 ms, given in 4 trains of 1 s duration at 10 s intervals) of the sciatic nerve, while the same stimulation couldn't induce LTP in sham-operated rats. The LTP could only be induced by high-frequency, high-intensity conditioning stimulation (100 Hz, 30-40 V, 0.5 ms, given in 4 trains of 1 s duration at 10 s intervals) of the sciatic nerve in these control rats. (2) The thresholds for evoking C-fiber dorsal horn field potentials were significantly lower and the amplitudes tended to be higher in neuropathic pain rats as compared to controls. CONCLUSION: These data suggest that the nerve injury itself is likely to induce a state of hyperexcitability at the spinal nociceptive synapses, and further support the notion that the long-term synaptic plasticity and the central sensitization may contribute to the development of neuropathic pain.

Animals↗
PubMed2005

Modulation of brain synaptic plasticity by steroid hormones.

Brain Synaptic plasticity has been studied extensively in the past decade. Alterations in synaptic plasticity are implicated in both normal brain functions and disorders. The molecular events leading to synaptogenesis or neurogenesis are being delineated. Several neurotransmitter receptors may be involved, but direct relation to NMDA receptors and BDNF peptides are suggested. Both genomic and non-genomic actions of steroid hormone on brain neurotransmission have been demonstrated. The direct action of neurosteroids to modulate neurotransmitter receptor binding and responses can be one of the mechanisms in the regulation of brain synaptic plasticity. Several lines of evidence in support of this hypothesis are reviewed in the present article.

Brain↗
PubMed2001

Back-propagating action potentials in pyramidal neurons: a putative signaling mechanism for the induction of Hebbian synaptic plasticity.

A hallmark of synaptic plasticity is the associative, or Hebbian, nature of its induction. By associative, we mean that the timing relationships between activity of the pre- and postsynaptic elements of a synapse determine whether synaptic strengths are modified. lt is well-established that associativity results, in large part, from the dual requirements for activation of the N-methyl-D-aspartate receptor-ionophore, namely presynaptic neurotransmitter release and postsynaptic depolarization. However, the specific dendritic events that provide the postsynaptic depolarization have been relatively unexplored. Increasing evidence suggests that back-propagating (i.e., antidromic) Na(+) action potentials provide the necessary postsynaptic depolarization to allow induction of associative synaptic plasticities. In hippocampal CAI and neocortical layer V pyramidal neurons, these action potentials provide much greater levels of dendritic depolarization than would be expected from synaptic currents alone. Moreover, they provide a relatively brief and synchronous depolarization throughout the dendritic arbor, allowing timing relationships to more directly reflect pre- and postsynaptic cell firing. Interestingly, certain properties of the back-propagating actions potentials differ from axonal or somatic action potentials in ways that seem to reflect their function. For example, the all-or-none property of action potential amplitude does not hold in the dendrites. In this review we discuss the back-propagating action potential as a dendritic signal that provides information to synapses about the firing state of the postsynaptic neuron. First, we consider the evidence that action potentials propagate back from the axon. Second, we describe the characteristics of the back-propagating action potential in terms of interactions of its underlying ionic currents. Third, we describe how these properties contribute to the timing aspects of the induction of long-term potentiation. Finally, we discuss modulation of the underlying ion channels by neurotransmitter systems and other agents and speculate on their roles in learning and memory.

Action Potentials↗
PubMed1993

Storage of a sensory pattern by anti-Hebbian synaptic plasticity in an electric fish.

Synaptic plasticity occurs in several regions of the vertebrate brain and is believed to mediate the storage of behaviorally significant information during learning. Synaptic plasticity is well demonstrated in most cases, but the behavioral meaning of the relevant neural signals and the behavioral role of the plasticity are uncertain. In this paper we describe a case of synaptic plasticity which involves identifiable sensory and motor signals and which appears to mediate the storage of an image of past sensory input. Corollary discharge signals associated with the motor command that drives the electric organ are prominent in the electrosensory lobe of mormyrid electric fish. Some of these corollary discharge signals elicit a negative image or representation of the electrosensory input pattern that has followed recent motor commands. When the temporal and spatial pattern of sensory input changes, the corollary discharge effect also changes in a corresponding manner. The cellular mechanisms by which the corollary discharge-evoked representation is stored were investigated by intracellular recording from cells of the electrosensory lobe and pairing intracellular current pulses with the corollary discharge signal. The results indicate that the representation of recent sensory input is stored by means of anti-Hebbian plasticity at the synapses between corollary discharge-conveying fibers and cells of the electrosensory lobe. The results also suggest that dendritic spikes and plasticity at inhibitory synapses are involved in the phenomenon.

Animals↗
PubMed2002

Computational studies on acquisition and adaptation of ocular following responses based on cerebellar synaptic plasticity.

To investigate how cerebellar synaptic plasticity guides the acquisition and adaptation of ocular following response (OFR), a large-scale network model was developed. The model includes the cerebral medial superior temporal area (MST), Purkinje cells (P cells) of the ventral paraflocculus, the accessory optic and climbing fiber systems, the brain stem oculomotor network, and the oculomotor plant. The model reconstructed temporal profiles of both firing patterns of MST neurons and P cells and eye movements. Model MST neurons (n = 1,080) were set to be driven by retinal error and exhibited 12 preferred directions, 30 preferred velocities, and 3 firing waveforms. Correspondingly, each model P cell contained 1,080 excitatory synapses from granule cell axons (GCA) and 1,080 inhibitory synapses. P cells (n = 40) were classified into four groups by their laterality (hemisphere) and by preferred directions of their climbing fiber inputs (CF) (contralateral or upward). The brain stem neural circuit and the oculomotor plant were modeled on the work of Yamamoto et al. The initial synaptic weights on the P cells were set randomly. At the beginning, P cell simple spikes were not well modulated by visual motion, and the eye was moved only slightly by the accessory optic system. The synaptic weights were updated according to integral-differential equation models of physiologically demonstrated synaptic plasticity: long-term depression and long-term potentiation for GCA synapses and rebound potentiation for inhibitory synapses. We assumed that maximum plasticity was induced when GCA inputs preceded CF inputs by 200 ms. After more than 10,000 presentations of ramp-step visual motion, the strengths of both the excitatory and inhibitory synapses were modified. Subsequently, the simple spike responses became well developed, and ordinary OFRs were acquired. The preferred directions of simple spikes became the opposite of those of CFs. Although the model MST neurons were set to possess a wide variety of firing characteristics, the model P cells acquired only downward or ipsilateral preferred directions, high preferred velocities and stereotypical firing waveforms. Therefore the drastic transition of the neural representation from the population codes in the MST to the firing-rate codes of simple spikes were learned at the GCA-P cell synapses and inhibitory cells-P cell synapses. Furthermore, the model successfully reproduced the gain- and directional-adaptation of OFR, which was demonstrated by manipulating the velocity and direction of visual motion, respectively. When we assumed that synaptic plasticity could only occur if CF inputs preceded GCA inputs, the ordinary OFR were acquired but neither the gain-adaptation nor the directional adaptation could be reproduced.

Adaptation, Physiological↗
PubMed2003

Mitochondrial regulation of synaptic plasticity in the hippocampus.

Synaptic mechanisms of plasticity are calcium-dependent processes that are affected by dysfunction of mitochondrial calcium buffering. Recently, we observed that mice deficient in mitochondrial voltage-dependent anion channels, the outer component of the mitochondrial permeability transition pore, have impairments in learning and hippocampal synaptic plasticity, suggesting that the mitochondrial permeability transition pore is involved in hippocampal synaptic plasticity. In this study, we examined the effect on synaptic transmission and plasticity of blocking the permeability transition pore with low doses of cyclosporin A and found a deficit in synaptic plasticity and an increase in base-line synaptic transmission. Calcium imaging of presynaptic terminals revealed a transient increase in the resting calcium concentration immediately upon incubation with cyclosporin A that correlated with the changes in synaptic transmission and plasticity. The effect of cyclosporin A on presynaptic calcium was abolished when mitochondria were depolarized prior to cyclosporin A exposure, and the effects of cyclosporin A and mitochondrial depolarization on presynaptic resting calcium were similar, suggesting a mitochondrial locus of action of cyclosporin A. To further characterize the calcium dynamics of the mitochondrial permeability transition pore, we used an in vitro assay of calcium handling by isolated brain mitochondria. Cyclosporin A-exposed mitochondria buffered calcium more rapidly and subsequently triggered a more rapid mitochondrial depolarization. Similarly, mitochondria lacking the voltage-dependent anion channel 1 isoform depolarized more readily than littermate controls. The data suggest a role for the mitochondrial permeability transition pore and voltage-dependent anion channels in mitochondrial synaptic calcium buffering and in hippocampal synaptic plasticity.

Animals↗
PubMed2006

Brain-derived neurotrophic factor mechanisms and function in adult synaptic plasticity: new insights and implications for therapy.

Synaptic plasticity, the fiundamental ability of synapses to undergo experience-dependent changes in synaptic strength, is thought to underlie a range of long-term adaptive responses of the central nervous system. The inability to generate or maintain appropriate changes in synaptic connectivity and neuronal circuitry is likely to impair cognitive futnction associated with many neurological and psychiatric disorders. The success of intervening therapeutic approaches will depend on the ability to target key component mechanisms in the complex process of synaptic plasticity. Brain-derived neurotrophic factor (BDNF) has emerged as a major regulator of synaptic plasticity and a key target in disorders such as major depression and Alzheimner's disease. This review discusses findings that link BDNF mechanisms in synaptic plasticity to disease mechanisms and possible future therapies.

Alzheimer Disease↗
PubMed2006

RNA binding proteins and the regulation of neuronal synaptic plasticity.

Cognitive function and memory rely on synaptic plasticity - the ability of synapses to modify their strength in response to stimulation. Emerging evidence indicates that post-transcriptional gene regulation is necessary for synaptic plasticity at several levels: by increasing proteome diversity through alternative splicing, or by enabling activity-dependent regulation of mRNA localization, translation or degradation in the dendrite. Mouse knockout studies have linked three RNA-binding proteins, fragile X mental retardation protein, cytoplasmic polyadenylation element binding factor and neuro-oncological ventral antigen to specific aspects of synaptic plasticity. Specificity in the regulation of synaptic plasticity might, in part, relate to the functional coherence of proteins encoded by the RNA targets of each RNA-binding protein.

Alternative Splicing↗
PubMed2003

Structurally dissimilar antimanic agents modulate synaptic plasticity by regulating AMPA glutamate receptor subunit GluR1 synaptic expression.

A growing body of data from clinical and preclinical studies suggests that the glutamatergic system may represent a novel therapeutic target for severe recurrent mood disorders. Since synapse-specific glutamate receptor expression/localization is known to play critical roles in synaptic plasticity, we investigated the effects of mood stabilizers on AMPA receptor expression. Rats were treated chronically with lithium or valproate, hippocampal synaptosomes were isolated, and GluR1 levels were determined. Additionally, hippocampal neurons were prepared from E18 rat embryos and treated with lithium or valproate. Surface expression of GluR1 was determined using a biotinylation assay, and double-immunostaining with anti-GluR1 and anti-synaptotagmin antibodies was used to determine synaptic GluR1 levels. The AMPA receptor subunit GluR1 expression in hippocampal synaptosomes was significantly reduced by both chronic lithium and valproate. Overall, these studies show that AMPA receptor subunit GluR1 is a common target for two structurally highly dissimilar, but highly efficacious, mood stabilizers, lithium and valproate. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of mood disorders, and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.

Animals↗
PubMedDate not supplied

Roles for short-term synaptic plasticity in behavior.

Short-term synaptic plasticity is phylogenetically widespread in ascending sensory systems of vertebrate brains. Such plasticity is found at all levels of sensory processing, including in sensory cortices. The functional roles of this apparently ubiquitous short-term synaptic plasticity, however, are not well understood. Data obtained in midbrain electrosensory neurons of Eigenmannia suggest that this plasticity has at least two roles in sensory processing; enhancing low-pass temporal filtering and generating phase shifts used in processing moving sensory images. Short-term synaptic plasticity may serve similar roles in other sensory modalities, including vision.

Animals↗
PubMed2003

Synaptic plasticity in the oedematous human cerebral cortex.

Synaptic plastic changes are fundamental events which occur spontaneously during development, maturity and aging processes or can be induced by injury or trauma. To examine lesion-induced synaptic plasticity, cortical biopsies were taken from the frontal, parietal, temporal and occipital cortex of living patients during neurosurgical treatment of brain trauma, brain tumours and vascular malformations, and processed for transmission electron microscopy. Enlargement of both pre- and postsynaptic endings, irregularly shaped, lobulated, stellate and bifurcated presynaptic endings and conformational changes of dendritic spines were observed. Numerous flat, curved and invaginated axodendritic and axospinous asymmetric synapses were distinguished and a smaller proportion of axodendritic and axosomatic symmetric synapses. Activated or sensitized synapses showed numerous frontline spheroid synaptic vesicles, prominent dense presynaptic dense projections and increased length of synaptic membrane complex. Perforated synapses, multiple synapses and serial synapses were also found evincing synaptic splitting and formation of new synaptic connections. The overall images suggest increased number of excitatory circuits, which were correlated with the tonico-clonic convulsion or post-traumatic seizures observed in some patients. Numerous coated vesicles were observed in pre- and postsynaptic structures. Increased number of polyribosomes were found in the dendritic shafts. The dilated spine apparatus, the coated vesicles and the increased number of polyribosomes seem to represent a system for synthesis, transport and storage of synaptic proteins for the formation of new synapses. Coexisting synaptic plasticity and synaptic degeneration were observed in the patients under study. Dendritic and astrocyte synapse-like junctions were also characterized.

Adolescent↗
PubMed1993

Synaptic plasticity and perforated synapses: their relevance for an understanding of abnormal synaptic organization.

Perforated synapses refer to a synaptic type found in the central nervous system, and characterized by a discontinuous postsynaptic density when viewed in transverse sections; they are doughnut-shaped or horseshoe-shaped when viewed in en face views. They are large, and are considered to represent single synapses. In this review the evidence for their being intermediates in synaptic turnover is examined. In particular, the view that they originate from conventional, non-perforated synapses, enlarge, and subsequently split to give rise to a new generation of non-perforated synapses, is critically assessed. It is concluded that all the necessary stages in such a scheme have not been unequivocally demonstrated, and an alternative is considered. According to this, perforated and non-perforated synapses constitute separate populations from early in their development, each representing complementary forms of synaptic plasticity. It is further argued that the perforated synapse population can be subdivided into synapses with simple, discrete perforations, those with re-entrant zones, and those with a more complex fragmented form of organization. There is evidence that it is synapses of the latter type that are implicated in synaptic plasticity. An attempt is also made to discover whether the results of synaptic studies on both the normal ageing human brain and the brain in Alzheimer's disease, throw light on the role of perforated synapses in synaptic plasticity. It is suggested that there may be a loss of perforated synapses in Alzheimer's disease, although definitive data are required to test this possibility.

Age Factors↗
PubMed2003

The amygdala, synaptic plasticity, and fear memory.

The nature and mechanisms of synaptic plasticity in the amygdala and the relation of amygdaloid plasticity to behavior are exciting new areas of study in neuroscience. These issues were at the heart of presentations by Paul Chapman, Michael Fanselow, Patricia Shinnick-Gallagher, and Michael Rogawski in a session entitled "Long-Term Plasticity in Amygdala Synaptic Transmission" that was held at the conference featured in this volume. In this chapter, I briefly summarize these talks and give my perspective on the presentations as the session chair. I argue that we must first understand the role of the amygdala in learning and memory in order to understand the contribution of amygdaloid synaptic plasticity to behavior. Although it is generally agreed that the amygdala is involved in several forms of emotional learning and memory such as pavlovian fear conditioning, a recent debate has emerged concerning the precise role of the amygdala in learning versus performing fear responses. I discuss data from my laboratory that unravel this issue. I argue that the basolateral complex of the amygdala (BLA) normally plays an essential role in associative processes in fear conditioning. Nonetheless, rats with BLA lesions acquire and express conditional fear under some conditions. A neuroanatomical model that accounts for these data is presented.

Amygdala↗
PubMed2004

A single in-vivo exposure to delta 9THC blocks endocannabinoid-mediated synaptic plasticity.

Endogenous cannabinoids (eCB) mediate synaptic plasticity in brain regions involved in learning and reward. Here we show that in mice, a single in-vivo exposure to Delta 9-tetrahydrocannabinol (THC) abolishes the retrograde signaling that underlies eCB-mediated synaptic plasticity in both nucleus accumbens (NAc) and hippocampus in vitro. This effect is reversible within 3 days and is associated with a transient modification in the functional properties of cannabinoid receptors.

Animals↗
PubMed1999

Permissive role of interneurons in corticostriatal synaptic plasticity.

Two different forms of synaptic plasticity have been found at corticostriatal synapses: long-term depression (LTD) and long-term potentiation (LTP). Both these enduring changes in the efficacy of excitatory neurotransmission in the striatum have a major impact on the physiological activity of the basal ganglia and are triggered by the stimulation of complex and independent cascades of intracellular second messenger systems. Striatal LTD and LTP are evoked following the repetitive stimulation of corticostriatal fibers and are dependent on the glutamate ionotropic receptor subtype activated. Recent experimental evidence indicates that two different subtypes of interneurons attend in the correct processing of information flow arising from the cortex and leading to striatal LTD or LTP. Acetylcholine (Ach) and nitric oxide (NO) producing striatal interneurons, in fact, are activated by the cortex during the induction phase of striatal plasticity, and stimulate, in turn, the intracellular changes in projection neurons required for LTD or LTP. Interneurons, therefore, exerts a feed-forward control of the excitability of striatal projection neurons ensuring the coordinate expression of two alternative forms of synaptic plasticity at the same type of excitatory synapse.

Animals↗