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At least 1,639 records · Page 91Linked to original sources
PubMed2002

Postsynaptic endocannabinoid release is critical to long-term depression in the striatum.

The striatum functions critically in movement control and habit formation. The development and function of cortical input to the striatum are thought to be regulated by activity-dependent plasticity of corticostriatal glutamatergic synapses. Here we show that the induction of a form of striatal synaptic plasticity, long-term depression (LTD), is dependent on activation of the CB1 cannabinoid receptor. LTD was facilitated by blocking cellular endocannabinoid uptake, and postsynaptic loading of anandamide (AEA) produced presynaptic depression. The endocannabinoid necessary for striatal LTD is thus likely to be released postsynaptically as a retrograde messenger. These findings demonstrate a new role for endocannabinoids in the induction of long-term synaptic plasticity in a circuit necessary for habit formation and motor control.

Animals↗
PubMed2000

Regional and postnatal heterogeneity of activity-dependent long-term changes in synaptic efficacy in the dorsal striatum.

High-frequency activation of excitatory striatal synapses produces lasting changes in synaptic efficacy that may contribute to motor and cognitive functions. While some of the mechanisms responsible for the induction of long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic responses at striatal synapses have been characterized, much less is known about the factors that govern the direction of synaptic plasticity in this brain region. Here we report heterogeneous activity-dependent changes in the direction of synaptic strength in subregions of the developing rat striatum. Neurons in the dorsolateral region of the anterior striatum tended to express LTD after high-frequency afferent stimulation (HFS) in slices from animals aged P15-P34. However, HFS in dorsolateral striatum from P12-P14 elicited an N-methyl-D-aspartate (NMDA) receptor-dependent form of LTP. Synapses in the dorsomedial anterior striatum exhibited a propensity to express an NMDA-receptor dependent form of LTP across the entire developmental time period examined. The NMDA receptor antagonist (+/-)-2-amino-5-phosphopentanoic acid (APV) inhibited evoked excitatory postsynaptic potentials recorded in striatum obtained from P12-P15 rats but had little effect in striatum from older animals. The expression of multiple forms of synaptic plasticity in the striatum suggests mechanisms by which this brain region plays pivotal roles in the acquisition or encoding of some forms of motor sequencing and stereotypical behaviors.

2-Amino-5-phosphonovalerate↗
PubMedDate not supplied

Information processing with frequency-dependent synaptic connections.

The efficacy of synaptic transmission between two neurons changes as a function of the history of previous activations of the synaptic connection. This history dependence can be characterized by examining the dependence of transmission on the frequency of stimulation. In this framework synaptic plasticity can also be examined in terms of changes in the frequency dependence of transmission and not merely in terms of synaptic strength which constitutes only a linear scaling mechanism. Recent work shows that the frequency dependence of transmission determines the content of information transmitted between neurons and that synaptic modifications can change the content of information transmitted. Multipatch-clamp recordings revealed that the frequency dependence of transmission is potentially unique for each synaptic connection made by a single axon and that the class of pre-postsynaptic neuron determines the class of frequency dependence (activity independent), while the unique activity relationship between any two neurons could determine the precise values of the parameters within a specific class (activity dependent). The content of information transmitted between neurons is also formalized to provide synaptic transfer functions which can be used to determine the role of the synaptic connection within a network of neurons. It is proposed that deriving synaptic transfer functions is crucial in order to understand the link between synaptic transmission and information processing within networks of neurons and to understand the link between synaptic plasticity and learning and memory.

Algorithms↗
PubMed2003

Ubiquitin-mediated proteasome activity is required for agonist-induced endocytosis of GluRs.

Recent studies documenting a role for local protein synthesis in synaptic plasticity have lead to interest in the opposing process, protein degradation, as a potential regulator of synaptic function. The ubiquitin-conjugation system identifies, modifies, and delivers proteins to the proteasome for degradation. We found that both the proteasome and ubiquitin are present in the soma and dendrites of hippocampal neurons. As the trafficking of glutamate receptors (GluRs) is thought to underlie some forms of synaptic plasticity, we examined whether blocking proteasome activity affects the agonist-induced internalization of GluRs in cultured hippocampal neurons. Treatment with the glutamate agonist AMPA induced a robust internalization of GluRs. In contrast, brief pretreatment with proteasome inhibitors completely prevented the internalization of GluRs. To distinguish between a role for the proteasome and a possible diminution of the free ubiquitin pool, we expressed a chain elongation defective ubiquitin mutant (UbK48R), which causes premature termination of polyubiquitin chains but, importantly, can serve as a substrate for mono-ubiquitin-dependent processes. Expression of K48R in neurons severely diminished AMPA-induced internalization establishing a role for the proteasome. These data demonstrate the acute (e.g., minutes) regulation of synaptic function by the ubiquitin-proteasome pathway in mammalian neurons.

Animals↗
PubMed1998

Calcium-evoked dendritic exocytosis in cultured hippocampal neurons. Part I: trans-Golgi network-derived organelles undergo regulated exocytosis.

Exocytosis is a widely observed cellular mechanism for delivering transmembrane proteins to the cell surface and releasing signaling molecules into the extracellular space. Calcium-evoked exocytosis, traditionally thought to be restricted to presynaptic specializations in neurons, has been described recently in many cells. Here, calcium-evoked dendritic exocytosis (CEDE) is visualized in living cultured hippocampal neurons. Organelles that undergo CEDE are in somata, dendrites, and perisynaptic regions, identified by using immunocytochemistry and correlative light and electron microscopy. CEDE is regulated developmentally: neurons <9 d in vitro do not show CEDE. In addition, CEDE is blocked by tetanus toxin, an inhibitor of regulated exocytosis, and nocodazole, an inhibitor of microtubule polymerization. Organelles that undergo CEDE often are found on the base of spines, putative sites of synaptic plasticity. CEDE therefore could be involved in structural and functional modification of spines and could play a role in synaptic plasticity, where it might involve changes in receptor/channel density, release of active compounds having effect on pre- and postsynaptic function, and/or growth of synaptic structures.

Animals↗
PubMed2003

Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction.

The neuropathological correlates of Alzheimer's disease (AD) include amyloid-beta (Abeta) plaques and neurofibrillary tangles. To study the interaction between Abeta and tau and their effect on synaptic function, we derived a triple-transgenic model (3xTg-AD) harboring PS1(M146V), APP(Swe), and tau(P301L) transgenes. Rather than crossing independent lines, we microinjected two transgenes into single-cell embryos from homozygous PS1(M146V) knockin mice, generating mice with the same genetic background. 3xTg-AD mice progressively develop plaques and tangles. Synaptic dysfunction, including LTP deficits, manifests in an age-related manner, but before plaque and tangle pathology. Deficits in long-term synaptic plasticity correlate with the accumulation of intraneuronal Abeta. These studies suggest a novel pathogenic role for intraneuronal Abeta with regards to synaptic plasticity. The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.

Alzheimer Disease↗
PubMed2004

Activation of protein kinase B (Akt) signaling after electroconvulsive shock in the rat hippocampus.

Akt (protein kinase B, PKB) is one of the major downstream pathways of neurotrophin signaling and plays important roles in the cell survival and synaptic plasticity of the central nervous system. Electroconvulsive shock (ECS) has neurotrophic effect and it affects the synaptic plasticity. It can activate another major pathway of neurotrophin signaling, i.e., Ras-Raf-MEK-Erk cascade. In this paper, the authors investigated whether ECS can activate Akt signaling in the rat hippocampus. After a single ECS, the phosphorylation of Akt was increased, as were the signals detected by phospho-PDK1 substrate antibody, which suggests the activation of PDK1, an upstream molecule of Akt. The phosphorylation of downstream molecules of Akt, forkhead transcription factors (FKHR), endothelial nitric oxide synthase (eNOS), and glycogen synthase kinase-3beta (GSK-3beta) was also increased. The increased phosphorylation of Akt appeared within 5 min of ECS and its time frame paralleled that of the phosphorylation of Erks. Taken together, these results suggest that ECS activates Akt signaling over a similar time scale to that of Erks in the rat hippocampus.

Animals↗
PubMed2004

Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation.

We have identified truncating mutations in the human DLG3 (neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation. DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family. Neuronal SAP102 is expressed during early brain development and is localized to the postsynaptic density of excitatory synapses. It is composed of three amino-terminal PDZ domains, an src homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains interact directly with the NR2 subunits of the NMDA glutamate receptor and with other proteins responsible for NMDA receptor localization, immobilization, and signaling. The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways. NMDA receptors have been implicated in the induction of certain forms of synaptic plasticity, such as long-term potentiation and long-term depression, and these changes in synaptic efficacy have been proposed as neural mechanisms underlying memory and learning. The disruption of NMDA receptor targeting or signaling, as a result of the loss of SAP102, may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations.

Base Sequence↗
PubMed2005

Stargazin reduces desensitization and slows deactivation of the AMPA-type glutamate receptors.

The AMPA-type glutamate receptors mediate the majority of the fast excitatory synaptic transmission and critically contribute to synaptic plasticity in the brain, hence the existence of numerous trafficking proteins dedicated to regulation of their synaptic delivery and turnover. Stargazin (also termed gamma2) is a member of a recently identified protein family termed transmembrane AMPA receptor regulatory proteins (TARPs). TARPs physically associate with AMPA receptors and participate in their surface delivery and anchoring at the postsynaptic membrane. Here, we report that next to its trafficking roles, stargazin may also act as a positive allosteric modulator of AMPA receptor ion channel function. Coexpression of stargazin with AMPA receptor subunits, either in Xenopus oocytes or in human embryonic kidney 293 cells, significantly reduced receptor desensitization in response to glutamate. Receptor deactivation rates were also slowed, and the recovery from desensitization was accelerated. Structurally, based on the data showing a tight correlation between desensitization and the stability of the AMPA receptor intradimer interface, we propose that binding of stargazin may stabilize the receptor conformation. Functionally, our data suggest that AMPA receptors complexed with stargazin (and possibly also with other TARPs) at the postsynaptic membrane are significantly more responsive to synaptically released glutamate compared with AMPA receptors lacking stargazin/TARP interaction. The putative existence of such two states of synaptic AMPA receptors, with and without stargazin/TARP binding, may provide a novel mechanism for regulation of excitatory synaptic strength during development and/or in synaptic plasticity in the adult brain.

Animals↗
PubMed1992

[Genetical responses of neuronal cells to synaptic transmission].

To understand the cellular mechanisms that lead to the generation of synaptic plasticity of neuronal cells, it is important to understand the intracellular responses of neuronal cells stimulated via synaptic transmission. The stimulation of mouse cerebellar granule cells via NMDA (N-methyl-D-aspartate) receptors caused an increase in deoxyribonucleic acid (DNA)-binding activities to TRE (12-O-tetradecanoylphorbol-13-acetate-responsive element) and CRE (adenosine 3',5'-cyclic monophosphate-responsive element) motifs, depending upon the presence of extracellular Ca2+. The increases in TRE- and CRE-binding activities were also detected with the stimulation of non-NMDA receptors by kainate. The increases in TRE- and CRE-binding activities were both mediated by the same DNA-binding complexes whose binding affinity to CRE was about three-fold higher than that to TRE. On the other hand, the stimulation of neuroblastoma x glioma hybrid NG108-15 via muscarinic acetylcholine receptors, alpha 2-adrenergic receptors and bradykinin receptors caused a rapid induction of zif/268. An additive effect on the induction of zif/268 was observed when the different stimuli were simultaneously added. Thus, it is extremely likely that signals transduced via synaptic transmission are transferred to the level of gene expression and evoke some events which might contribute to the generation of synaptic plasticity in neuronal cells. In addition, we have found that the direct injection of plasmid DNAs into mouse skeletal muscle with fructose, glucose or NaCl solution led to a long-term expression of the introduced gene in muscle cells.

Animals↗
PubMed2005

Different types of environmental enrichment have discrepant effects on spatial memory and synaptophysin levels in female mice.

Environmental enrichment paradigms that incorporate cognitive stimulation, exercise, and motor learning benefit memory and synaptic plasticity across the rodent lifespan. However, the contribution each individual element of the enriched environment makes to enhancing memory and synaptic plasticity has yet to be delineated. Therefore, the current study tested the effects of three of these elements on memory and synaptic protein levels. Young female C57BL/6 mice were given 3h of daily exposure to either rodent toys (cognitive stimulation) or running wheels (exercise), or daily acrobatic training for 6 weeks prior to and throughout behavioral testing. Controls were group housed, but did not receive enrichment. Spatial working and reference memory were tested in a water-escape motivated radial arm maze. Levels of the presynaptic protein synaptophysin were then measured in frontoparietal cortex, hippocampus, striatum, and cerebellum. Exercise, but not cognitive stimulation or acrobat training, improved spatial working memory relative to controls, despite the fact that both exercise and cognitive stimulation increased synaptophysin levels in the neocortex and hippocampus. These data suggest that exercise alone is sufficient to improve working memory, and that enrichment-induced increases in synaptophysin levels may not be sufficient to improve working memory in young females. Spatial reference memory was unaffected by enrichment. Acrobat training had no effect on memory or synaptophysin levels, suggesting a minimal contribution of motor learning to the mnemonic and neuronal benefits of enrichment. These results provide the first evidence that different elements of the enriched environment have markedly distinct effects on spatial memory and synaptic alterations.

Animals↗
PubMed2003

Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain.

The induction of associative synaptic plasticity in the mammalian central nervous system classically depends on coincident presynaptic and postsynaptic activity. According to this principle, associative homosynaptic long-term potentiation (LTP) of excitatory synaptic transmission can be induced only if synaptic release occurs during postsynaptic depolarization. In contrast, heterosynaptic plasticity in mammals is considered to rely on activity-independent, non-associative processes. Here we describe a novel mechanism underlying the induction of associative LTP in the lateral amygdala (LA). Simultaneous activation of converging cortical and thalamic afferents specifically induced associative, N-methyl-D-aspartate (NMDA)-receptor-dependent LTP at cortical, but not at thalamic, inputs. Surprisingly, the induction of associative LTP at cortical inputs was completely independent of postsynaptic activity, including depolarization, postsynaptic NMDA receptor activation or an increase in postsynaptic Ca2+ concentration, and did not require network activity. LTP expression was mediated by a persistent increase in the presynaptic probability of release at cortical afferents. Our study shows the presynaptic induction and expression of heterosynaptic and associative synaptic plasticity on simultaneous activity of converging afferents. Our data indicate that input specificity of associative LTP can be determined exclusively by presynaptic properties.

Amygdala↗
PubMed1999

Chronic inhibition of NOS does not prevent plasticity of rat somatosensory (S1) cortex following deafferentation.

Nitric oxide (NO) has been proposed as an intercellular messenger mediating postsynaptic to presynaptic information transfer in the induction of long-term potentiation. A number of studies support the possible involvement of NO in synaptic plasticity. NO may have a role in synaptogenesis and synaptic plasticity in developing rat brain and may play a fundamental part in the process of regeneration, plasticity, and retargeting of axons following injury. We examined the possible role of NO on plasticity in the rat first somatosensory cortex with [14C]2-deoxyglucose (2-DG) autoradiography in rats treated daily with l-nitroarginine (l-NA) following neonatal unilateral vibrissae deafferentation. After 6 weeks of l-NA treatment, the local cerebral glucose utilization (LCGU) and the spatial extent of the metabolic activation following stimulation of the spared whisker was measured. NOS catalytic activity exhibited significant inhibition throughout the treatment period. Vibrissae deafferentation produced a small but not statistically significant increase of LCGU in the vibrissa activated C3 barrel, and l-NA treatment did not alter the activation of LCGU in the deafferented cortex following whisker stimulation. Additionally, l-NA treatment did not alter the area of metabolic activation on either the non-deafferented side or the deafferented side. Deafferentation produced a 298% increase in the metabolic representation of the spared C3 barrel following stimulation in the saline treated animals, a 257% increase in the chronically l-NA treated animals, and a 256% increase in the short-term treated animals, all with respect to the response in the non-deafferented cortex. Metabolic plasticity in the barrel cortex was not attenuated by l-NA treatment. These results show that nitric oxide does not play a major role on developmental cortical plasticity induced by vibrissae deafferentation in the rat.

Afferent Pathways↗
PubMed1986

Translocation of protein kinase C activity may mediate hippocampal long-term potentiation.

Protein kinase C activity in rat hippocampal membranes and cytosol was determined 1 minute and 1 hour after induction of the synaptic plasticity of long-term potentiation. At 1 hour after long-term potentiation, but not at 1 minute, protein kinase C activity was increased twofold in membranes and decreased proportionately in cytosol, suggesting translocation of the activity. This time-dependent redistribution of enzyme activity was directly related to the persistence of synaptic plasticity, suggesting a novel mechanism regulating the strength of synaptic transmission.

Animals↗
PubMed1996

Long-term depression properties in a simple system.

Long-term depression (LTD) in pairs of cultured rodent hippocampal neurons was examined to study the molecular basis of this form of synaptic plasticity. We have previously characterized two components of transmitter release: a synchronous, fast phase that requires synaptotagmin I, and an asynchronous, slow component that persists in the absence of synaptotagmin I. Are these two release components differentially affected by the presynaptic changes of LTD, or is the mechanism of plasticity common to both? We find that LTD is expressed as parallel changes in the fast and slow components of release, and that this form of synaptic plasticity is still seen in the absence of functional synaptotagmin I. Any alterations in the presynaptic release machinery observed during LTD thus involve mechanisms shared by both modes of release.

Animals↗
PubMed1998

Experience-dependent plasticity of adult rat S1 cortex requires local NMDA receptor activation.

The effect of blocking NMDA glutamate receptors in adult rat cortex on experience-dependent synaptic plasticity of barrel cortex neurons was studied by infusing D-AP5 with an osmotic minipump over barrel cortex for 5 d of novel sensory experience. In acute pilot studies, 500 microM D-AP5 was shown to specifically suppress NMDA receptor (NMDAR)-dependent responses of single cells in cortical layers I-IV. To induce plasticity, all whiskers except D2 and D1 were cut close to the face 1 d after pump insertion. The animals were housed with 2 cage mates before recording 4 d later. This pairing of two whiskers for several days in awake animals generates highly significant biases in responses from D2 layer IV (barrel) cells to the intact D1 whisker as opposed to the cut D3 whisker. D-AP5 completely prevented the D1/D3 surround whisker bias from occurring in the D2 barrel cells (p > 0.6 for D1 > D3, Wilcoxon). Fast-spike and slow-spike barrel cells were affected equally, suggesting parity for inhibitory and excitatory cell plasticity. D-AP5 only partially suppressed the D1/D3 bias in supragranular layers (layers II-III) in the same penetrations (p < 0.042 for D1 > D3). In control animals, the inactive L-AP5 isomer allowed the bias to develop normally toward the intact surround whisker (p < 0.001 for D1 > D3) for cells in all layers. We conclude that experience-dependent synaptic plasticity of mature barrel cortex is cortically dependent and that modification of local cortical NMDARs is necessary for its expression.

2-Amino-5-phosphonovalerate↗
PubMed2002

What can the hippocampal representation of environmental geometry tell us about Hebbian learning?

The importance of the hippocampus in spatial representation is well established. It is suggested that the rodent hippocampal network should provide an optimal substrate for the study of unsupervised Hebbian learning. We focus on the firing characteristics of hippocampal place cells in morphologically different environments. A hard-wired quantitative geometric model of individual place fields is reviewed and presented as the framework in which to understand the additional effects of synaptic plasticity. Existent models employing Hebbian learning are also reviewed. New information is presented regarding the dynamics of place field plasticity over short and long time scales in experiments using barriers and differently shaped walled environments. It is argued that aspects of the temporal dynamics of stability and plasticity in the hippocampal place cell representation both indicate modifications to, and inform the nature of, the synaptic plasticity in place cell models. Our results identify a potential neural basis for long-term incidental learning of environments and provide strong constraints for the way the unsupervised learning in cell assemblies envisaged by Hebb might occur within the hippocampus.

Action Potentials↗