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PubMed2000

Glutamatergic components underlying lead-induced impairments in hippocampal synaptic plasticity.

Epidemiological investigations have established the relationship between chronic developmental lead (Pb) exposure and cognitive impairments in young children, defining Pb neurotoxicity as a significant pediatric health problem. Exposed animals have proven to be effective models of this condition, exhibiting similar sensitivity to the actions of Pb and replicating abnormal learning behaviors in exposed children. Research has extended these observations in animals to identifying the processes underlying the cognitive dysfunction, utilizing the long-term potentiation (LTP) paradigm as a correlate of learning ability. Results from these studies have been in widespread agreement in reporting impairments in synaptic plasticity. Exposure-related changes consist of increases in LTP induction threshold, decreases in magnitude of potentiation, and shortened LTP duration. Furthermore, while LTP may be more readily affected by Pb during early development, exposure initiated after weaning also potently affects synaptic plasticity. Biphasic dose-effect relationships also appear in which impaired LTP is observed at intermediate exposure levels (27-62 microg/100 ml), but not at higher exposures. Investigation of the synaptic processes underlying LTP has provided additional insight into the bases of the impaired potentiation and diminished cognitive ability. Biochemical and neurophysiological approaches have found stimulated glutamate release to be diminished in hippocampus at blood Pb values where deficits in LTP have been observed. Multiple actions of Pb may be involved at this exposure level since animals exposed postweaning exhibited similar decrements in evoked glutamate release to those exposed continuously from conception, similar to the observations in measures of LTP. A biphasic dose-effect relationship was also found in which stimulated glutamate release in hippocampus was decreased at intermediate exposures, but not at higher levels. A direct inhibitory effect of Pb2+ on NMDA receptor function does not appear to occur at environmentally relevant exposure levels, but both exposure-induced increases and decreases in receptor density have been reported by different workers. Evidence from behavioral and neurophysiological investigations can be explained by increased NMDA receptor density on the bases of increased sensitivity to agonists and decreased sensitivity to antagonists. From this body of findings it is apparent that decreases in stimulated glutamate release are a significant contributing factor to the exposure-related changes seen in LTP. Furthermore, despite general agreement on the actions of Pb on synaptic plasticity, reports of exposure effects on NMDA receptor function have been relatively variable, suggesting either that the nature of the receptor changes are dependent on exposure conditions or that the receptors are secondarily affected by Pb actions produced at signal transduction or cellular loci.

Animals↗
PubMed2000

Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity.

Bidirectional changes in the efficacy of neuronal synaptic transmission, such as hippocampal long-term potentiation (LTP) and long-term depression (LTD), are thought to be mechanisms for information storage in the brain. LTP and LTD may be mediated by the modulation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazloe proprionic acid) receptor phosphorylation. Here we show that LTP and LTD reversibly modify the phosphorylation of the AMPA receptor GluR1 subunit. However, contrary to the hypothesis that LTP and LTD are the functional inverse of each other, we find that they are associated with phosphorylation and dephosphorylation, respectively, of distinct GluR1 phosphorylation sites. Moreover, the site modulated depends on the stimulation history of the synapse. LTD induction in naive synapses dephosphorylates the major cyclic-AMP-dependent protein kinase (PKA) site, whereas in potentiated synapses the major calcium/calmodulin-dependent protein kinase II (CaMKII) site is dephosphorylated. Conversely, LTP induction in naive synapses and depressed synapses increases phosphorylation of the CaMKII site and the PKA site, respectively. LTP is differentially sensitive to CaMKII and PKA inhibitors depending on the history of the synapse. These results indicate that AMPA receptor phosphorylation is critical for synaptic plasticity, and that identical stimulation conditions recruit different signal-transduction pathways depending on synaptic history.

Animals↗
PubMed1998

Neural circuits for taste. Excitation, inhibition, and synaptic plasticity in the rostral gustatory zone of the nucleus of the solitary tract.

The rostral nucleus of the solitary tract (rNST) plays a key role in modulating, organizing and distributing the sensory information arriving at the central nervous system from gustatory receptors. However, except for some anatomical studies of rNST synapses, the neural circuits responsible for this first stage in synaptic processing of taste information are largely unknown. Over the past few years we have used an in vitro brain slice preparation of the rNST to study synaptic processing, and it has become apparent that the rNST is a very complex neural relay. Synaptic potentials recorded in rNST neurons resulting from stimulation of afferent taste fibers are a composite of excitatory and inhibitory post synaptic potentials. Pure excitatory postsynaptic potentials (EPSP) can be isolated by using gamma-aminobutyric acid type A (GABAA) receptor blockers to eliminate the inhibitory postsynaptic potentials (IPSP). Application of glutamate ionotropic receptor blockers effectively eliminates all postsynaptic activity, indicating that glutamate is the transmitter at the first central synapse in the taste pathway. Stimulation of the afferent taste fibers originating from the anterior (chorda tympani) and posterior (glossopharyngeal) tongue results in a postsynaptic potential that is a complex sum of the two individual potentials. Thus, rNST neurons receive convergent synaptic input from the anterior and posterior tongue. The IPSP component of the synaptic potentials in rNST results from stimulation of interneurons. If these IPSPs are initiated by tetanic stimulation they undergo both short-term and long-term changes. Short-term changes result in the development of biphasic depolarizing IPSPs, and long-term changes result in potentiation of the IPSPs that can last over an hr in some neurons. This remarkable synaptic plasticity may be involved in the mechanism of learned taste behaviors. Synaptic transmission in rNST consists of excitation combined with inhibition. The inhibition does not simply depress excitation but probably serves many roles such as shaping and limiting excitation, coordinating the timing of synaptic events and participating in synaptic plasticity. Knowledge of these synaptic mechanisms is essential to understanding how the rNST processes taste information.

Animals↗
PubMedDate not supplied

Regional differences of serotonin-mediated synaptic plasticity in the chicken spinal cord with development and aging.

Previous studies in our laboratory [3,17] have demonstrated that serotonin (5-HT) appears to have a trophic-like effect in enhancing synapse formation and maintenance in both the developing and the adult central nervous system. In the present study, we focused on age-related changes in the density of the axosomatic and axodendritic synapses and the number of 5-HT-positive fibers in the chicken spinal cord, with special reference to differences between the ventral (laminae VII and IX) and the dorsal (lamina I) horn. At 1 week posthatching (P1W), a transient overproduction of synapses and 5-HT-immunoreactive fibers occurred in lamina IX; all parameters had returned to their initial levels by 1 month post-hatching (P1M). The density of synapses further decreased by about 40% between P6M and P2Y (2 years posthatching). Although the magnitude of the transient increase in lamina VII was less than that in lamina IX, the changing pattern of the synapses and the 5-HT-positive fibers was similar in both regions. In the ventral horn, thin 5-HT-positive fibers were most prominent at P1W and then decreased with development; thin 5-HT-positive fibers were still found at P6M but had almost disappeared by P2Y. By contrast, at P2Y the density of the synapses and the 5-HT-positive fibers in the dorsal horn was even higher than that of younger animals. Reduction of 5-HT levels in P2Y-old chickens by p-chlorophenylalanine (pCPA) administration decreased the synaptic density in lamina I but not in lamina IX. The results of this study demonstrate that 5-HT-mediated synaptic plasticity is markedly different in the ventral and dorsal horns of the aged chicken. In the ventral horn, synaptic plasticity reached a maximum at about P1W, remained stable in the young-adult period, and then finally disappeared in the aged chicken. Conversely, the results suggest that in the dorsal horn, 5-HT fibers continue to mediate the trophic influence on synaptic plasticity even in the old chicken.

Aging↗
PubMed1997

Synaptic plasticity in hippocampal interneurons? A commentary.

The hypothesis that excitatory synapses onto hippocampal inhibitory interneurons undergo forms of synaptic plasticity similar to that observed in principal pyramidal neurons has received much attention in the last few years. No general consensus exists, however, concerning the presence (or absence) of long-term potentiation and depression in nonpyramidal neurons. A large source of this disagreement stems from the experimental paridigms chosen to elicit synaptic plasticity in the various studies, since most of the induction protocols used did not permit the separation of plasticity occurring on principal cells from possible direct plasticity on the interneurons themselves. In this commentary we discuss some of the issues surrounding these data and also address some of the technical considerations one must address before the presence or absence of long-term potentiation in interneurons can be answered unequivocally.

Hippocampus↗
PubMed1992

Synaptic plasticity in the dentate gyrus of aged rats is altered after chronic nimodipine application.

We examined ultrastructural correlates of synaptic plasticity in the hippocampus of young (3 months) vs aged (30 months) Wistar rats and established the effects of the calcium antagonist nimodipine in animals chronically treated from 24 to 30 months. The effects of nimodipine was studied since this compound improves hippocampal neuronal physiology and enhances cognitive function during aging. In the supragranular layer of the dentate gyrus we found a 24% decrease in synaptic density (Nv) in aged animals, while synaptic size (S) was not significantly altered. After nimodipine treatment Nv in aged rats was not significantly different from young adults, thus being significantly increased compared to age-matched controls. The size of synapses was not significantly altered after nimodipine administration. Total synaptic surface area (Sv) in nimodipine-treated animals was significantly increased compared to aged controls, however, Sv remained significantly lower than in young adults. These data indicate that chronic administration of nimodipine enables granular cells in the dentate gyrus to maintain its number of synaptic contacts during the aging process. Furthermore, the presented influence of nimodipine on synaptic plasticity processes may underlie previously reported improved cognitive functioning of aged animals treated similarly with nimodipine.

Aging↗
PubMed2000

Tissue plasminogen activator controls multiple forms of synaptic plasticity and memory.

Induction of long-term depression (LTD) in rat striatal slices revealed that this form of synaptic plasticity is coupled to an increased expression of tissue-plasminogen activator (t-PA) mRNA, as detected by the mRNA differential display technique. To further investigate the involvement of this gene in synaptic remodelling following striatal LTD, we recorded electrical activity from mice lacking the gene encoding t-PA (t-PA-KO) and from wild-type (WT) mice. Tetanic stimulation induced LTD in the large majority of striatal neurons recorded from WT mice. Conversely, LTD was absent in a significant proportion of striatal neurons obtained from mice lacking t-PA. Electrophysiological recordings obtained from hippocampal slices in the CA1 area showed that mainly the late phase of long-term potentiation (LTP) was reduced in t-PA-KO mice. Learning and memory-related behavioural abnormalities were also found in these transgenic mice. Disruption of the t-PA gene, in fact, altered both the context conditioning test, a hippocampus-related behavioural task, and the two-way active avoidance, a striatum-dependent task. In an open field object exploration task, t-PA-KO mice expressed deficits in habituation and reactivity to spatial change that are consistent with an altered hippocampal function. Nevertheless, decreased rearing and poor initial object exploration were also observed, further suggesting an altered striatal function. These data indicate that t-PA plays a critical role in the formation of various forms of synaptic plasticity and memory.

Animals↗
PubMed1996

[Dynamic regulation of the NMDA receptor channel subunits in the central nervous system and their involvement in synaptic plasticity and development].

The N-methyl-D-aspartate (NMDA) receptor channel plays a key role in activity-dependent synaptic plasticity in the central nervous system. The channel is also involved in neural development, including experience-dependent changes in neuro-behaviors and synaptic refinement. Molecular biological studies have revealed its heteromeric configuration, consisting of the epsilon (NR2) and zeta 1 (NR1) subunits. The zeta 1 subunit is an essential subunit component to form functional NMDA receptor channels, while four members of the epsilon subunits potentiate the channel activity and modulate the functional properties. In situ hybridization has elucidated distinct spatial and temporal expressions of each epsilon subunit, in contrast to ubiquitous and stable expression of the zeta 1 subunit. Furthermore, recent analyses with mutant mice defective in respective NMDA receptor subunits are providing direct evidence for their disparate physiological roles in synaptic plasticity and development. This review summarizes the recent progress from the molecular-anatomical point of view.

Animals↗
PubMed1993

Perforated axospinous synapses with multiple, completely partitioned transmission zones: probable structural intermediates in synaptic plasticity.

Analysis of axospinous synapses in the rat dentate gyrus, using three-dimensional reconstructions from electron micrographs of serial sections, revealed a novel synaptic subtype. Synapses of this subtype exhibit partitions that emanate from the postsynaptic spine head and invaginate the presynaptic axon terminal, dividing its portion contracted by the spine into distinct protrusions. Such complete spine partitions provide barriers between two to four discrete transmission zones, each one being formed by a separate axon terminal protrusion and delineated by a separate segment of the postsynaptic density (PSD). Spine partitions that differ from the complete ones were found in two other synaptic subtypes. One of these is characterized by a sectional partition the base of which is placed between the arms of a horseshoe-shaped PSD. Synapses of another subtype exhibit a focal partition the base of which is restricted to a perforation in a fenestrated PSD. Although both sectional and focal partitions invaginate a presynaptic axon terminal, they do not divide into separate protrusions and do not split a single transmission zone into disjointed entities. All three subtypes of partitioned synapses have nonpartitioned counterparts exhibiting segmented, horseshoe-shaped, or fenestrated PSDs. These observations suggest a model of structural modifications underlying synaptic plasticity. According to this model, synapses with multiple, completely partitioned transmission zones that appear to be designed as elements of an unusually high strength, represent pivotal structural intermediates in synaptic plasticity. The formation of such synapses from those that belong to other subtypes is postulated to result in a sustained increase in the efficacy of synaptic transmission. Conversely, a disassembly of complete partitions with the transformation of multiple transmission zones into a single one is proposed to lead to a persistent depression of synaptic responses.

Animals↗
PubMed2004

Modulation of synaptic plasticity by antimanic agents: the role of AMPA glutamate receptor subunit 1 synaptic expression.

Increasing data suggest that impairments of cellular plasticity underlie the pathophysiology of bipolar disorder. In this context, it is noteworthy that AMPA glutamate receptor trafficking regulates synaptic plasticity, effects mediated by signaling cascades, which are targets for antimanic agents. The present studies were undertaken to determine whether two clinically effective, but structurally highly dissimilar, antimanic agents lithium and valproate regulate synaptic expression of AMPA receptor subunit glutamate receptor 1 (GluR1). Chronic (but not acute) treatment of rats with therapeutically relevant concentrations of lithium or valproate reduced hippocampal synaptosomal GluR1 levels. The reduction in synaptic GluR1 by lithium and valproate was attributable to a reduction of surface GluR1 distribution onto the neuronal membrane as demonstrated by three independent assays in cultured hippocampal neurons. Furthermore, these agents induced a decrease in GluR1 phosphorylation at a specific PKA site (GluR1p845), which is known to be critical for AMPA receptor insertion. Sp-cAMP treatment reversed the attenuation of phosphorylation by lithium and valproate and also brought GluR1 back to the surface, suggesting that phosphorylation of GluR1p845 is involved in the mechanism of GluR1 surface attenuation. In addition, GluR1p845 phosphorylation also was attenuated in hippocampus from lithium- or valproate-treated animals in vivo. In contrast, imipramine, an antidepressant that can trigger manic episodes, increased synaptic expression of GluR1 in hippocampus in vivo. These studies suggest that regulation of glutamatergically mediated synaptic plasticity may play a role in the treatment of bipolar disorder and raise the possibility that agents more directly affecting synaptic GluR1 may represent novel therapies for this devastating illness.

Animals↗
PubMed1998

Hippocampal synaptic plasticity in mice overexpressing an embryonic subunit of the NMDA receptor.

The effects of changing NMDA receptor subunit composition on synaptic plasticity in the hippocampus were analyzed by creating transgenic mice overexpressing NR2D, a predominantly embryonic NMDA receptor subunit. NMDA-evoked currents in the transgenic mice had smaller amplitudes and slower kinetics. The transgenics also displayed age-dependent deficits in synaptic plasticity in area CA1 of the hippocampus. Long-term depression was selectively impaired in juvenile mice when NR2D overexpression was moderate. In mature mice, overexpression of NR2D was associated with a reduction of both NR2B and Ca2+-independent activity of Ca2+- and calmodulin-dependent protein kinase II. These biochemical changes were correlated with a marked impairment of NMDA-dependent long-term potentiation, but spatial behavior was normal in these mice. These results show that the developmental regulation of NMDA receptor subunit composition alters the frequency at which modification of synaptic responses occur after afferent stimulation.

2-Amino-5-phosphonovalerate↗
PubMed2000

Region-specific localization of glutamine synthetase immunoreactivity in the mouse olfactory bulb: implications for neuron-glia interaction in bulbar synaptic plasticity.

Glutamine synthetase (GS) critically regulates the metabolism of glutamate and gamma-amino butyric acid (GABA), which mediate synaptic plasticity in the olfactory bulb. In this study, GS immunolocalization in the mouse olfactory bulb was examined. The main and accessory subdivisions of the olfactory bulb possess GS-positive cells and processes in the plexiform-, the mitral- and the granule cell layers. GS has been demonstrated to show a predominantly astrocytic localization; its presence in the cell layers implicated in glutamatergic and GABAergic function therefore suggests that bulbar synaptic plasticity in mice may be regulated by astroglia and, together with other lines of evidence, point to the possibility of a functional astroglia-neuron system in the mouse olfactory bulb.

Animals↗
PubMed2002

Fibronectin domains of extracellular matrix molecule tenascin-C modulate hippocampal learning and synaptic plasticity.

The extracellular matrix molecule tenascin-C (TN-C) has been shown to be involved in hippocampal synaptic plasticity in vitro. Here, we describe a deficit in hippocampus-dependent contextual memory in TN-C-deficient mice using the step-down avoidance paradigm. We further show that a fragment of TN-C containing the fibronectin type-III repeats 6-8 (FN6-8), but not a fragment containing repeats 3-5, bound to pyramidal and granule cell somata in the hippocampal formation of C57BL/6J mice and repelled axons of pyramidal neurons when presented as a border in vitro. Injection of the FN6-8 fragment into the hippocampus inhibited retention of memory in the step-down paradigm and reduced levels of long-term potentiation in the CA1 region of the hippocampus. In summary, our data show that TN-C is involved in hippocampus-dependent contextual memory and synaptic plasticity and identify the FN6-8 domain as one of molecular determinants mediating these functions.

Animals↗
PubMed2001

Effects of ginsenoside Rg1 on synaptic plasticity of freely moving rats and its mechanism of action.

AIM: To investigate the effect and mechanism of ginsenoside Rg1 on synaptic plasticity of freely moving rats. METHODS: SD rats were chronically implanted with a stimulation electrode in the perforant path (PP) of hippocampus and a recording electrode in the granule cell of dentate gyrus. After administration of ginsenoside Rg(1) (10, 30 mg/kg, ip) for 12 d, extracellular recording technique was used to record the population spike (PS). Mossy fiber (MF) sprouting was measured using Timm's staining, and an immunohistochemical technique was used to detect the expression of presynaptic growth-associated protein 43 (GAP-43). RESULTS: Rg1 could significantly increase the sensitivity of evoking PS, the amplitude of PS and induce PP-DG long-term potentiation (LTP) in the dentate gyrus (DG) of freely moving rats. In the meantime, Rg1 accelerated MF sprouting in CA3 cell field of hippocampus. The expression level of GAP-43 was elevated in granule cell layer and hilus of DG of Rg1-treated rats. CONCLUSION: The increased synaptic plasticity may attribute to the increased expression of GAP-43 in granule cell layer of DG and the onset of the sprouting of granule cell axon-MF. The MF sprouting accelerated the synaptic transmission in positive-feedback. Their interaction and the synergism is part of the mechanisms underlying the nootropic effect of Rg1.

Animals↗
PubMed2002

Age-dependent differential regulation of genes encoding APP and alpha-synuclein in hippocampal synaptic plasticity.

We investigated the modulation of the messenger RNA encoding the amyloid precursor protein (APP) and alpha-synuclein following induction of long-term potentiation (LTP) in the dentate gyrus of young and aged rats. Three hours after tetanic stimulation, LTP induced in the young rats was maintained; the aged rats, however, fell into two subgroups: those in which LTP was maintained, and those in which LTP had declined to basal levels. In young rats, the global expression of mRNAs of all isoforms of APP and in particular that of the isoform lacking the KPI domain were significantly upregulated. In aged rats, the global expression of mRNAs of all isoforms of APP was not modified, regardless of whether LTP was maintained or not. The level of mRNA encoding the Kunitz protease-inhibitory (KPI)-minus isoform of APP, however, was increased in aged rats in which LTP was maintained, suggesting that the gene of this isoform may be more specifically regulated by synaptic plasticity. In contrast, we found that the gene encoding alpha-synuclein showed a trend towards being downregulated at the mRNA level in young rats following LTP, and significantly so in aged rats in which LTP was maintained, whereas it was not downregulated in aged rats with decremental LTP. These data suggest that the regulated expression of APP isoforms is part of the tanscriptional response associated with the enduring forms of synaptic plasticity and is altered with age. Whereas the level of alpha-synuclein mRNA is not apparently modified in normal LTP, it may reflect a mechanism of apoptotic cell death in aging that is in part responsible for decremental synaptic plasticity.

Aging↗
PubMed1996

[Postsynaptic density proteins related to the expression and modulation of synaptic plasticity].

One approach to elucidate the mechanism of synaptic plasticity, especially the postsynaptic mechanism, is the analysis of postsynaptic density (PSD). The PSD is an electron-dense cytoskeletal structure apposing the postsynaptic membrane, is a specific device for postsynaptic signal transmission, and attaches a number of molecules that are involved in postsynaptic signal transmission and its regulation. I review in this article the two groups of PSD proteins: Protein kinases (Ca2+/calmodulin-dependent protein kinase II, protein kinase C, mitogen-activated protein kinase, and tyrosine kinases) and molecules that work as messengers from the synapse to the nucleus (MSNs). Protein phosphorylation-dephosphorylation plays a pivotal role in the modulation of synaptic transmission, especially in the early phase of long-term potentiation (LTP). On the other hand, regulation of LTP at a late phase is governed by the new gene expression that is induced by synaptic inputs. For the altered gene expression, synaptic information must be transmitted from the synapse to the nucleus. I have started the search for the MSNs just recently. In this review, I describe several MSN candidates, especially NF-kappa B-like and I kappa B-like molecules.

Animals↗
PubMedDate not supplied

Spike-based synaptic plasticity and the emergence of direction selective simple cells: mathematical analysis.

In the companion paper we presented extended simulations showing that the recently observed spike-timing dependent synaptic plasticity can explain the development of simple cell direction selectivity (DS) when simultaneously modifying the synaptic strength and the degree of synaptic depression. Here we estimate the spatial shift of the simple cell receptive field (RF) induced by the long-term synaptic plasticity, and the temporal phase advance caused by the short-term synaptic depression in response to drifting grating stimuli. The analytical expressions for this spatial shift and temporal phase advance lead to a qualitative reproduction of the frequency tuning curves of non-directional and directional simple cells. In agreement with in vivo recordings, the acquired DS is strongest for test gratings with a temporal frequency around 1-4 Hz. In our model this best frequency is determined by the width of the learning function and the time course of depression, but not by the temporal frequency of the 'training' stimuli. The analysis further reveals the instability of the initially symmetric RF, and formally explains why direction selectivity develops from a non-directional cell in a natural, directionally unbiased stimulation scenario.

Animals↗
PubMed2004

Regenerative dendritic spikes and synaptic plasticity.

During the last decade, our vision of the neuronal dendritic tree has changed from a simple input device conducting afferent input as a passive cable to the cell soma to a series of independent and actively operating processing units. Different voltage- and ligand-gated ion channels located in the dendritic tree not only participate in processing afferent inputs but also enable the dendritic tree to initiate regenerative spikes, traditionally considered to be exclusively restricted to axonal structures. Recent results suggest that these local dendritic spikes may act as a means to initiate long-term synaptic plasticity. Different from Hebbian synaptic plasticity this type of induction does not need axonal action potential firing and backpropagation into the dendrite. This new proximity learning rule, first postulated by neural network theorists, may have large significance for the information processing in the brain.

Action Potentials↗