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Results for “synaptic plasticity”

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PubMed1999

The polo-like protein kinases Fnk and Snk associate with a Ca(2+)- and integrin-binding protein and are regulated dynamically with synaptic plasticity.

In order to stabilize changes in synaptic strength, neurons activate a program of gene expression that results in alterations of their molecular composition and structure. Here we demonstrate that Fnk and Snk, two members of the polo family of cell cycle associated kinases, are co-opted by the brain to serve in this program. Stimuli that produce synaptic plasticity, including those that evoke long-term potentiation (LTP), dramatically increase levels of both kinase mRNAs. Induced Fnk and Snk proteins are targeted to the dendrites of activated neurons, suggesting that they mediate phosphorylation of proteins in this compartment. Moreover, a conserved C-terminal domain in these kinases is shown to interact specifically with Cib, a Ca(2+)- and integrin-binding protein. Together, these studies suggest a novel signal transduction mechanism in the stabilization of long-term synaptic plasticity.

Amino Acid Sequence↗
PubMed2000

Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington's disease mutation.

Huntington's disease (HD) is an autosomal dominant progressive and fatal neurodegenerative brain disorder caused by an expanded CAG/polyglutamine repeat in the coding region of the gene. Presymptomatic Huntington's disease patients often exhibit cognitive deficits before the onset of classical symptoms. To investigate the possibility that changes in synaptic plasticity might underlie cognitive impairment in HD, we examined hippocampal synaptic plasticity and spatial cognition in a transgenic mouse (R6/2 line) expressing exon 1 of the human Huntington's disease gene containing an expanded CAG repeat. This mouse exhibits a progressive and fatal neurological phenotype that resembles Huntington's disease. We report that R6/2 mice show marked alterations in synaptic plasticity at both CA1 and dentate granule cell synapses, and impaired spatial cognitive performance in the Morris water maze. The changes in hippocampal plasticity were age dependent, appearing at CA1 synapses several weeks before they were observed in the dentate gyrus. Deficits in synaptic plasticity at CA1 synapses occurred before an overt phenotype. This suggests that altered synaptic plasticity contributes to the pre-symptomatic changes in cognition reported in human carriers of the Huntington' disease gene. The temporal and regional changes in synaptic plasticity within the hippocampus mirror the appearance of neuronal intranuclear inclusions, suggesting a relationship between polyglutamine aggregation and dysfunction.

Action Potentials↗
PubMed1995

Metabotropic glutamate receptors and visual cortical synaptic plasticity.

Two forms of use-dependent synaptic plasticity, called long-term potentiation (LTP) and long-term depression (LTD), can be elicited in the visual cortex following different paradigms of electrophysiological stimulation. These neurobiological phenomena often are considered as necessary components of models for the alteration in function of the nervous system that must occur at some level for the establishment and (or) maintenance of memory engrams, for learning processes, or for the consolidation of active neural connections and regression of inactive contacts in the developing brain. It has been postulated that for LTP and LTD to be produced in the hippocampus, activation of a particular subtype of excitatory amino acid receptor, the metabotropic receptor, is a critical requirement. Only recently has it become possible to test this hypothesis directly, as a new compound, (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG), has been introduced and the suggestion made that it selectively antagonizes the metabotropic receptor. This substance has been tested in the present study on responses recorded from slices of rat visual cortex and has been found both to block the activation of the metabotropic receptor and to interfere selectively with the form of synaptic plasticity called LTD. It thus appears from the experiments reported in this paper as though the metabotropic receptor subtype that is blocked by MCPG is required for the expression of LTD but not for the expression of LTP, in the visual cortex of adult rats.

Animals↗
PubMed2004

Ubiquitin-proteasome-mediated local protein degradation and synaptic plasticity.

A proteolytic pathway in which attachment of a small protein, ubiquitin, marks the substrates for degradation by a multi-subunit complex called the proteasome has been shown to function in synaptic plasticity and in several other physiological processes of the nervous system. Attachment of ubiquitin to protein substrates occurs through a series of highly specific and regulated steps. Degradation by the proteasome is subject to multiple levels of regulation as well. How does the ubiquitin-proteasome pathway contribute to synaptic plasticity? Long-lasting, protein synthesis-dependent, changes in the synaptic strength occur through activation of molecular cascades in the nucleus in coordination with signaling events in specific synapses. Available evidence indicates that ubiquitin-proteasome-mediated degradation has a role in the molecular mechanisms underlying synaptic plasticity that operate in the nucleus as well as at the synapse. Since the ubiquitin-proteasome pathway has been shown to be versatile in having roles in addition to proteolysis in several other cellular processes relevant to synaptic plasticity, such as endocytosis and transcription, this pathway is highly suited for a localized role in the neuron. Because of its numerous roles, malfunctioning of this pathway leads to several diseases and disorders of the nervous system. In this review, I examine the ubiquitin-proteasome pathway in detail and describe the role of regulated proteolysis in long-term synaptic plasticity. Also, using synaptic tagging theory of synapse-specific plasticity, I provide a model on the possible roles and regulation of local protein degradation by the ubiquitin-proteasome pathway.

Animals↗
PubMed2003

Cellular and molecular connections between sleep and synaptic plasticity.

The hypothesis that sleep promotes learning and memory has long been a subject of active investigation. This hypothesis implies that sleep must facilitate synaptic plasticity in some way, and recent studies have provided evidence for such a function. Our knowledge of both the cellular neurophysiology of sleep states and of the cellular and molecular mechanisms underlying synaptic plasticity has expanded considerably in recent years. In this article, we review findings in these areas and discuss possible mechanisms whereby the neurophysiological processes characteristic of sleep states may serve to facilitate synaptic plasticity. We address this issue first on the cellular level, considering how activation of T-type Ca(2+) channels in nonREM sleep may promote either long-term depression or long-term potentiation, as well as how cellular events of REM sleep may influence these processes. We then consider how synchronization of neuronal activity in thalamocortical and hippocampal-neocortical networks in nonREM sleep and REM sleep could promote differential strengthening of synapses according to the degree to which activity in one neuron is synchronized with activity in other neurons in the network. Rather than advocating one specific cellular hypothesis, we have intentionally taken a broad approach, describing a range of possible mechanisms whereby sleep may facilitate synaptic plasticity on the cellular and/or network levels. We have also provided a general review of evidence for and against the hypothesis that sleep does indeed facilitate learning, memory, and synaptic plasticity.

Animals↗
PubMed1994

The role of calcium-calmodulin kinase II in three forms of synaptic plasticity.

BACKGROUND: Calcium influx into postsynaptic dendritic spines can, depending on circumstances, activate three forms of synaptic plasticity: long-term potentiation (LTP), short-term potentiation (STP) and long-term depression (LTD). The increased postsynaptic calcium concentrations that trigger all three forms of plasticity should activate the alpha isoform of calcium-calmodulin kinase type II (alpha CaMKII), which is present at high levels just below the postsynaptic membrane. Earlier experiments have implicated alpha CaMKII in the regulation or induction of LTP, but no information is available on the possible role of this enzyme in the two other forms of synaptic plasticity, STP and LTD. RESULTS: We used mice that lack the gene for alpha CaMKII to investigate the role of this enzyme in synaptic plasticity. Field potential recordings from hippocampal slices taken from mutant mice show that STP and LTD are, like LTP, absent or markedly attenuated in the absence of alpha CaMKII. A brief form of synaptic modification--post-tetanic potentiation (PTP)--is, however, intact in the absence of this enzyme. CONCLUSIONS: It appears likely that alpha CaMKII is involved in the production or global regulation of all three forms of synaptic plasticity. We propose that the activation of this enzyme is a common step in the induction of LTP and STP, and that alpha CaMKII activity is required for the normal production of LTD.

2-Amino-5-phosphonovalerate↗
PubMed1997

Contrasting forms of synaptic plasticity in monkey inferotemporal and primary visual cortices.

Activity-dependent synaptic plasticity was examined in vivo in two cortical areas of the adult monkey visual system, the primary visual and inferotemporal cortex, the first and late cortical stages essential for object recognition. Discontinuous high-frequency electrical stimulation of intrinsic horizontal connections in layer 2/3 caused contrasting forms of synaptic plasticity in the two areas. In the inferotemporal cortex, long-term potentiation of extracellular field potentials in layer 2/3 was induced, whereas in the same pathway of V1, identical stimulation protocol elicited long-term depression. The results indicate that susceptibility to synaptic plasticity varies among cortical areas in the monkey brain.

Animals↗
PubMed2003

Traumatic brain injury and its effects on synaptic plasticity.

Animal models have been used to simulate the effects of human head trauma. Some of these models have been further utilized to explore how trauma affects specific mechanisms of synaptic plasticity, a cellular model for memory consolidation. Unfortunately, these studies have been more limited in number in spite of their importance for understanding alterations in synaptic plasticity and memory impairments in trauma patients. Research in this area includes well characterized trauma models, genetically engineered animals and neuroprotective studies. One largely ignored but important idea that is entertained here is that trauma may be a crucial aetiological factor for the loss of potassium homeostasis. Moreover, high extracellular potassium has been shown to promote abnormal expression of hippocampal synaptic plasticity due to K(+)-induced glutamate release, thus showing important relationships among trauma, glia, potassium and synaptic plasticity. Collectively, this mini review surveys investigations of head trauma involving altered mechanisms of synaptic plasticity and how trauma may be related to increased risk for dementia.

Alzheimer Disease↗
PubMed2001

Models of brain injury and alterations in synaptic plasticity.

Animal models are crucial for understanding human pathophysiological processes and for understanding how connections are injured, lost, or even regenerated and/or repaired. When animal models are used in conjunction with theoretical computational models, an ideal combination is achieved that potentially yields insight and encourages the formation of new theories concerning connectionism, cognitive functioning, and synaptic mechanisms. Mechanisms regulating glutamate receptor activation and intracellular calcium levels are important for normal synaptic transmission. These mechanisms (and others) are also critical during and after brain injury when the potential exists for these mechanisms to function pathologically. Interestingly enough, the regulation of glutamate receptor activation and intracellular calcium levels is also involved in normal processes of neuronal and synaptic plasticity. In addition, studies have shown that neurotrophins and cytokines, which are released after brain injury, can be neuroprotective and may also be important in synaptic plasticity. Furthermore, synaptic plasticity is a phenomenon thought by many to be necessary for memory encoding. If this is the case, then research described in this review has significant scientific merit concerning plasticity and memory and clinical benefit for understanding pathophysiologic processes associated with brain injury and memory impairment. This paper reviews the application of experimental animal models of brain injury for simulating conditions of stroke, trauma, and epilepsy (and/or seizure generation) and the associated cellular mechanisms of brain injury. The paper also briefly addresses the advantage of using computational models in combination with experimental models for hypothesis building and for aiding in the interpretation of empirical data. Finally, it reviews studies concerning brain injury and synaptic plasticity.

Animals↗
PubMed2004

Presynaptic CaMKII is necessary for synaptic plasticity in cultured hippocampal neurons.

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional enzyme that is very critical for synaptic plasticity and memory formation. Although significant progress has been made in understanding the role of postsynaptic CaMKII in synaptic plasticity, very little is known about its presynaptic function during plasticity changes. Here we report that KN-93, a membrane-permeable CaMKII inhibitor, blocked glutamate-induced increases in the frequency of miniature excitatory postsynaptic currents (mEPSCs) and the number of presynaptic functional boutons in cultured hippocampal pyramidal neurons. In addition, presynaptic injection of the membrane-impermeable CaMKII inhibitor peptide 281-309 blocked synaptic plasticity induced by tetanus, glutamate, or NO/cGMP pathway activation as expressed by long-lasting increases in EPSC amplitude and functional presynaptic boutons. Presynaptic injection of CaMKII itself coupled with weak tetanus produced an immediate and long-lasting enhancement of EPSC amplitude. Thus, the present results conclusively prove that presynaptic CaMKII is essential for synaptic plasticity in cultured hippocampal neurons.

2-Amino-5-phosphonovalerate↗
PubMed2002

Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding.

Activity-dependent changes in neuronal excitability and synaptic strength are thought to underlie memory encoding. In hippocampal CA1 neurons, small conductance Ca2+-activated K+ (SK) channels contribute to the afterhyperpolarization, affecting neuronal excitability. In the present study, we examined the effect of apamin-sensitive SK channels on the induction of hippocampal synaptic plasticity in response to a range of stimulation frequencies. In addition, the role of apamin-sensitive SK channels on hippocampal-dependent memory encoding and retention was also tested. The results show that blocking SK channels with apamin increased the excitability of hippocampal neurons and facilitated the induction of synaptic plasticity by shifting the modification threshold to lower frequencies. This facilitation was NMDA receptor (NMDAR) dependent and appeared to be postsynaptic. Mice treated with apamin demonstrated accelerated hippocampal-dependent spatial and nonspatial memory encoding. They required fewer trials to learn the location of a hidden platform in the Morris water maze and less time to encode object memory in an object-recognition task compared with saline-treated mice. Apamin did not influence long-term retention of spatial or nonspatial memory. These data support a role for SK channels in the modulation of hippocampal synaptic plasticity and hippocampal-dependent memory encoding.

Action Potentials↗
PubMed2001

A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus.

Many forms of long-lasting behavioral and synaptic plasticity require the synthesis of new proteins. For example, long-term potentiation (LTP) that endures for more than an hour requires both transcription and translation. The signal-transduction mechanisms that couple synaptic events to protein translational machinery during long-lasting synaptic plasticity, however, are not well understood. One signaling pathway that is stimulated by growth factors and results in the translation of specific mRNAs includes the rapamycin-sensitive kinase mammalian target of rapamycin (mTOR, also known as FRAP and RAFT-1). Several components of this translational signaling pathway, including mTOR, eukaryotic initiation factor-4E-binding proteins 1 and 2, and eukaryotic initiation factor-4E, are present in the rat hippocampus as shown by Western blot analysis, and these proteins are detected in the cell bodies and dendrites in the hippocampal slices by immunostaining studies. In cultured hippocampal neurons, these proteins are present in dendrites and are often found near the presynaptic protein, synapsin I. At synaptic sites, their distribution completely overlaps with a postsynaptic protein, PSD-95. These observations suggest the postsynaptic localization of these proteins. Disruption of mTOR signaling by rapamycin results in a reduction of late-phase LTP expression induced by high-frequency stimulation; the early phase of LTP is unaffected. Rapamycin also blocks the synaptic potentiation induced by brain-derived neurotrophic factor in hippocampal slices. These results demonstrate an essential role for rapamycin-sensitive signaling in the expression of two forms of synaptic plasticity that require new protein synthesis. The localization of this translational signaling pathway at postsynaptic sites may provide a mechanism that controls local protein synthesis at potentiated synapses.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity.

The regulated delivery of AMPA-type glutamate receptors (AMPARs) to synapses is an important mechanism underlying synaptic plasticity. Here, we ask whether the synaptic scaffolding protein PSD-95 (postsynaptic density 95) participates in AMPAR incorporation during two forms of synaptic plasticity. In hippocampal slice cultures, the expression of PSD-95-green fluorescent protein (PSD-95-GFP) increases AMPAR currents by selectively delivering glutamate receptor 1 (GluR1)-containing receptors to synapses, thus mimicking long-term potentiation (LTP). Mutational analysis shows that the N terminal of PSD-95 including the first two PDZ [PSD-95/Discs large (Dlg)/zona occludens-1 (ZO-1)] domains is necessary and sufficient to mediate this effect. Further supporting a role in synaptic plasticity, wild-type PSD-95 occludes LTP and dominant negative forms block LTP. Moreover, we demonstrate that PSD-95 also participates in AMPAR delivery during experience-driven plasticity in vivo. In the barrel cortex from experience-deprived animals, the expression of PSD-95-GFP selectively increases AMPAR currents, mimicking experience-driven plasticity. In nondeprived animals, PSD-95-GFP produces no additional potentiation, indicating common mechanisms between PSD-95-mediated potentiation and experience-driven synaptic strengthening. A dominant negative form of PSD-95 blocks experience-driven potentiation of synapses. Pharmacological analysis in slice cultures reveals that PSD-95 acts downstream of other signaling pathways involved in LTP. We conclude that PSD-95 controls activity-dependent AMPAR incorporation at synapses via PDZ interactions not only during LTP in vitro but also during experience-driven synaptic strengthening by natural stimuli in vivo.

Animals↗
PubMed2002

Spike-timing dependent synaptic plasticity: a phenomenological framework.

In this paper a phenomenological model of spike-timing dependent synaptic plasticity (STDP) is developed that is based on a Volterra series-like expansion. Synaptic weight changes as a function of the relative timing of pre- and postsynaptic spikes are described by integral kernels that can easily be inferred from experimental data. The resulting weight dynamics can be stated in terms of statistical properties of pre- and postsynaptic spike trains. Generalizations to neurons that fire two different types of action potentials, such as cerebellar Purkinje cells where synaptic plasticity depends on correlations in two distinct presynaptic fibers, are discussed. We show that synaptic plasticity, together with strictly local bounds for the weights, can result in synaptic competition that is required for any form of pattern formation. This is illustrated by a concrete example where a single neuron equipped with STDP can selectively strengthen those synapses with presynaptic neurons that reliably deliver precisely timed spikes at the expense of other synapses which transmit spikes with a broad temporal distribution. Such a mechanism may be of vital importance for any neuronal system where information is coded in the timing of individual action potentials.

Action Potentials↗
PubMed2005

Synaptic plasticity in micropatterned neuronal networks.

Synaptic plasticity is thought to be of central importance for information processing by the nervous system. Additionally, specific neuronal connectivity patterns in the brain are implicated to play a role in the perception, processing and storage of incoming signals. Experimental control over connectivity within functional neuronal networks is therefore a promising approach in research on signal transduction and processing by the nervous system. A cell culture system is presented that allows experimental determination of neuronal connectivity patterns in an in vitro network. Rat embryonic cortical neurons were grown on patterns of extracellular matrix proteins applied to polystyrene substrates by microcontact printing. Cells comply well with the pattern and form synaptic connections along the experimentally defined pathways. Chemical synapses identified by double patch-clamp measurement showed paired pulse depression as well as frequency-dependent depression in response to trains of stimuli. This type of short-term plasticity has similarly been reported by others in brain slices. Thus, the system reproduces features central for neuronal information processing while the architecture of the network is experimentally manipulable. The ability to tailor the geometry of functional neuronal networks offers a valuable tool both for fundamental questions in neuroscientific research and a wide range of biotechnological applications.

Action Potentials↗
PubMed1999

Kainate receptors are involved in synaptic plasticity.

The ability of synapses to modify their synaptic strength in response to activity is a fundamental property of the nervous system and may be an essential component of learning and memory. There are three classes of ionotropic glutamate receptor, namely NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid) and kainate receptors; critical roles in synaptic plasticity have been identified for two of these. Thus, at many synapses in the brain, transient activation of NMDA receptors leads to a persistent modification in the strength of synaptic transmission mediated by AMPA receptors. Here, to determine whether kainate receptors are involved in synaptic plasticity, we have used a new antagonist, LY382884 ((3S, 4aR, 6S, 8aR)-6-((4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydro isoquinoline-3-carboxylic acid), which antagonizes kainate receptors at concentrations that do not affect AMPA or NMDA receptors. We find that LY382884 is a selective antagonist at neuronal kainate receptors containing the GluR5 subunit. It has no effect on long-term potentiation (LTP) that is dependent on NMDA receptors but prevents the induction of mossy fibre LTP, which is independent of NMDA receptors. Thus, kainate receptors can act as the induction trigger for long-term changes in synaptic transmission.

Animals↗
PubMed1983

Evidence for synaptic plasticity in the cerebellar cortex.

The learning machine model of the cerebellum by Marr and Albus contains a special type of synaptic plasticity. Experimental evidence for this synaptic plasticity has been meager, but very recently positive evidence has become available. Ito, Sakurai and Tongroach (7) demonstrated the occurrence of a long-lasting depression in mossy fiber responsiveness of Purkinje cells subsequent to conjuctive stimulation of mossy fibers and climbing fibers. A similar long-lasting depression was shown to occurred in sensitivity of Purkinje cell dendrites to a putative neurotransmitter of parallel fibers, i.e., glutamate. Furthermore, Ito and Kano (6) produced a long-lasting depression in the molecular layer of the cerebellar cortex by simultaneous direct stimulation of parallel fibers and climbing fibers. These long-lasting depressions appear to represent a synaptic plasticity of the form proposed by Albus.

Animals↗
PubMed1996

Glia-neuron intercommunications and synaptic plasticity.

It is established that astrocytes are the intimate partner of neurons throughout their lifespan. However, astrocytes play different roles at different stages of the lifespan. During neurogenesis and early development, glial cells provide a scaffold for the correct migration of neurons and growth cones. They provide guidance cues and may also be involved in neuronal proliferation. In the adult, astrocytes maintain neuronal homeostasis and synaptic plasticity. This review discusses some of the cell-cell communication signals which are involved in the maintenance of synaptic plasticity. They are divided into: (a) glia-to-glia signaling, which involves non-synaptic communication by coupling of astrocytes. In this cell communication, cytoplasmic exchange of ions and small molecules among cells is accomplished through cell coupling of cells via cell-to-cell contacts, termed gap junctions; (b) neuron-to-glia signaling, which involves synaptic interactions. This cell-cell intercommunication has received considerable attention. Of special interest is the role of astrocytes in glutamic acid compartmentation and in preventing glutamic acid neurotoxicity. A glutamate-induced calcium signaling appears to be involved in this neuron-astrocyte interaction. The intriguing possibility is that neuronally induced astrocyte calcium signals may feed back to influence neuronal excitability or regulate synaptic transmission; (c) signals from astrocytes to neurons: a new concept of neuron-glia intercommunication. As mentioned, calcium appears to be the molecule in this glia-neuron signaling, although glial cell receptor-mediated signals are involved also. Receptor interactions on astrocytes through a cascade of events lead to modification in the extracellular concentration of glutamate. The role of astrocytes in synaptic plasticity is not as well understood during ageing and their role in neuronal cell death during ageing and neurodegeneration can only be speculated. However, astrocytes in the aged brain exhibit various receptors, including glutamate receptors. Thus, astrocytes can be expected to modify the expression of endogenous neurotoxins and thus contribute to synaptic plasticity in ageing. Synaptic plasticity continues to be a homeostatic relationship between neurons and glial cells. The possibility of signaling from astrocytes to neurons has opened new horizons for glial cell function and new challenges of research for gliobiologists.

Animals↗