SEARCH · PubMed Health

Results for “Neuronal Plasticity”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 559 records · Page 31Linked to original sources

PubMed2002

Modulation of synaptic plasticity by stress and antidepressants.

Recent preclinical and clinical studies have shown that mechanisms underlying neuronal plasticity and survival are involved in both the outcome of stressful experiences and the action of antidepressants. Whereas most antidepressants predominantly affect the brain levels of monoamine neurotransmitters, it is increasingly appreciated that they also modulate neurotransmission at synapses using the neurotransmitter glutamate (the most abundant in the brain). In the hippocampus, a main area of the limbic system involved in cognitive functions as well as attention and affect, specific molecules enriched at glutamatergic synapses mediate major changes in synaptic plasticity induced by stress paradigms or antidepressant treatments. We analyze here the modifications induced by stress or antidepressants in the strength of synaptic transmission in hippocampus, and the molecular modifications induced by antidepressants in two main mediators of synaptic plasticity: the N-methyl-D-aspartate (NMDA) receptor complex for glutamate and the Ca2+/calmodulin-dependent protein kinase II (CaM kinase II). Both stress and antidepressants induce alterations in long-term potentiation of hippocampal glutamatergic synapses, which may be partly accounted for by the influence of environmental or drug-induced stimulation of monoaminergic pathways projecting to the hippocampus. In the course of antidepressant treatments significant changes have been described in both the NMDA receptor and CaM kinase II, which may account for the physiological changes observed. A central role in these synaptic changes is exerted by brain-derived neurotrophic factor (BDNF), which modulates both synaptic plasticity and its molecular mediators, as well as inducing morphological synaptic changes. The role of these molecular effectors in synaptic plasticity is discussed in relation to the action of antidepressants and the search for new molecular targets of drug action in the therapy of mood disorders.

Animals↗

PubMedDate not supplied

Preliminary evidence: decreased GAP-43 message in tangle-bearing neurons relative to adjacent tangle-free neurons in Alzheimer's disease parahippocampal gyrus.

Loss of synapses has been shown to correlate with the severity of dementia in Alzheimer's disease (AD). Intracellular neurofibrillary tangles (NFTs) have also been shown to correlate to the severity of AD dementia. We have been investigating the influence of NFTs on mRNAs related to neuronal plasticity and synaptic function. We recently reported a decrease in message for the plasticity marker, GAP-43, in AD cases with high tangle densities. The study did not permit us to determine if: a) the decrease in GAP-43 message was specific to the NFT-bearing neurons, b) a general decrease in GAP-43 message was occurring in all surviving neurons, or c) the decrease in GAP-43 message was due to a loss of neurons. It is unlikely a loss of neurons could explain the sixfold GAP-43 message loss we reported, because only a 19% excess decrease in density of hippocampal neurons occurs in AD cases with high tangle densities. Consequently, the study reported here was undertaken to determine if a general decrease in GAP-43 message was occurring in all surviving AD neurons or if the decrease in GAP-43 message was specific to NFT-bearing neurons. We combined immunocytochemistry for neurofibrillary tangles with in situ hybridization for GAP-43 message. We report here preliminary evidence indicating a decrease in GAP-43 message in NFT-bearing neurons compared to adjacent nontangle bearing neurons in parahippocampal cortex of AD patients.

Alzheimer Disease↗

PubMed2002

Localization and regulation of the tissue plasminogen activator-plasmin system in the hippocampus.

The extracellular protease cascade of tissue plasminogen activator (tPA) and plasminogen has been implicated in neuronal plasticity and degeneration. We show here that unstimulated expression of tPA in the mouse hippocampus is concentrated in the mossy fiber pathway, with little or no expression within the perforant path, the Schaffer collaterals, or neuronal cell bodies. tPA protein is also expressed in vascular endothelial cells throughout the brain parenchyma. Four hours after excitotoxic injury, tPA protein is transiently induced within CA1 pyramidal neurons. The induced CA1 tPA is localized to neurons that survive the injury and is enzymatically active. Within the mossy fiber pathway, injury resulted in decreased tPA protein. In contrast, mossy fiber tPA activity displayed a biphasic character: transient increase at 8 hr, then a decrease by 24 hr after injury. Analysis of plasminogen activator inhibitor-1 (PAI-1) expression showed that PAI-1 antigen is upregulated by 24 hr and could account for the tPA activity downregulation seen at this time point. Plasminogen immunohistochemistry suggested an increase within the mossy fiber pathway after injury. Finally, hippocampal tPA expression among various mammalian species was strikingly different. These results indicate a complex control of tPA protein and enzymatic activity in the hippocampus that may help regulate neuronal plasticity.

Animals↗

PubMedDate not supplied

Learning by neurones: role of attention, reinforcement and behaviour.

The importance of the behavioural situation, attentional demands of the task, and stimulus-reinforcement contingencies in promoting or permitting experience-dependent neuronal plasticity is argued. Evidence is provided for the specific activation of the locus coeruleus noradrenergic system of the rat by novel stimuli encountered while investigating the environment, as well as during a formal learning situation. Noradrenergic neurons are particularly concerned with changes in the predictive value of the stimulus, when new learning should occur. Noradrenaline, released at LC terminals in target sensory systems, could facilitate shifts in attention, information processing and memory through its well-documented gating and tuning effects and its permissive role in long-term potentiation. Dopamine neurons, which fire persistently to reward during learning, could be involved in maintaining the behavioural response.

Animals↗

PubMed2003

Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior.

Although neuronal stress circuits have been identified, little is known about the mechanisms that underlie the stress-induced neuronal plasticity leading to fear and anxiety. Here we found that the serine protease tissue-plasminogen activator (tPA) was upregulated in the central and medial amygdala by acute restraint stress, where it promoted stress-related neuronal remodeling and was subsequently inhibited by plasminogen activator inhibitor-1 (PAI-1). These events preceded stress-induced increases in anxiety-like behavior of mice. Mice in which the tPA gene has been disrupted did not show anxiety after up to three weeks of daily restraint and showed attenuated neuronal remodeling as well as a maladaptive hormonal response. These studies support the idea that tPA is critical for the development of anxiety-like behavior after stress.

Amygdala↗

PubMedDate not supplied

SGK protein kinase facilitates the expression of long-term potentiation in hippocampal neurons.

Previous studies showed that the serum- and glucocorticoid-inducible kinase (sgk) gene plays an important role in long-term memory formation. The present study further examined the role of SGK in long-term potentiation (LTP). The dominant-negative mutant of sgk, SGKS422A, was used to inactivate SGK. Results revealed a time-dependent increase in SGK phosphorylation after tetanization with a significant effect observed 3 h and 5 h later. Transfection of SGKS422A impaired the expression, but not the induction, of LTP. Furthermore, the constitutively active sgk, SGKS422D, up-regulated postsynaptic density-95 expression in the hippocampus. These results together support the role of SGK in neuronal plasticity.

Animals↗

PubMed2001

Plasticity: downstream of glutamate.

Glutamate neurotransmission is an essential component of many forms of neuronal plasticity, however, the intracellular mechanisms that mediate plasticity are only beginning to be elucidated. The emerging image of the NMDA receptor complex reminds us that the similarity between mechanisms of plasticity in various model systems is greater than their apparent differences. For example, the cAMP-dependent protein kinase A signalling pathway is crucial for plasticity in a variety of neuronal systems and across a wide variety of species.

Animals↗

PubMed2005

Remodelling of spinal nociceptive mechanisms in an animal model of monoarthritis.

Intra-articularly injected complete Freund's adjuvant creates in rats a chronic monoarthritis suitable for studying neuronal plasticity and chronic pain. Using such a model, we report electrophysiological and morphological evidence of alterations in somatosensory synaptic function. In arthritic rats, the baseline activity of dorsal spinal cord wide dynamic range or nociceptive-specific neurons was greater than in control animals. Moreover, neuronal responses elicited by an innocuous stimulation with von Frey filaments applied to the arthritic joint were greater in amplitude and produced the afterdischarge that normally characterizes a nociceptive response. In contrast to the response in control animals, passive movement of the arthritic joint produced an increase in the amplitude of the response of these neurons to iontophoretic application of glutamate receptor agonists over a time frame of 10-30 min. This potentiation was blocked by pretreatment with a neurokinin-1 (NK-1) receptor antagonist, suggesting the involvement of substance P. Ultrastructural analysis of the dorsal horn revealed that movement of the arthritic joint also induced NK-1 receptor internalization, indicative of nociception. Morphological examination revealed significantly increased expression of substance P and its receptor within the superficial dorsal horn of monoarthritic animals. These unique functional and chemical changes reflect alterations in both presynaptic and postsynaptic mechanisms in nociceptive transmission at the spinal level. Thus, although treatment of arthritis should obviously target its peripheral aetiology, targeting its central components is a logical therapeutic complementary objective.

Action Potentials↗

PubMed1992

The 5-HT4 receptor subtype inhibits K+ current in colliculi neurones via activation of a cyclic AMP-dependent protein kinase.

1. The aim of the present study was to examine the effect of 5-hydroxytryptamine (5-HT) on K+ current in primary culture of mouse colliculi neurones and to identify the 5-HT receptor subtype that could be involved in this effect. 2. The voltage-activated K+ current of the neurones was partially blocked by 8-bromo adenosine 3':5'-cyclic monophosphate (8-bromo-cyclic AMP). This effect was mimicked by 5-HT and the action of 5-HT could be antagonized by H7, a non specific protein kinase inhibitor, and by PKI, the specific cyclic AMP-dependent protein kinase blocker. 3. A similar cyclic AMP-dependent blockade of the K+ current was found with renzapride (BRL 24,924) and other 5-HT4 receptor agonists such as cisapride, BIMU 8, zacopride and 5-methoxytryptamine (5-MeOT). ICS 205,930, the classical 5-HT4 receptor blocker, could not be used in this study because it inhibited the studied K+ current by itself. However, the novel 5-HT4 receptor antagonist, DAU 6285 blocked the effects of 5-HT and renzapride on the K+ current. 4. The current was insensitive to the 5-HT1 and 5-HT3 receptor agonists (8-hydroxy-2-(di-n-propylamino) tetralin, RU 24,969, carboxamidotryptamine, 2-CH3-5-HT) as well as to 5-HT1, 5-HT2 and 5-HT3 antagonists (methiothepin, ketanserin, ondansetron [GR 38,032]). Moreover, these antagonists did not affect the actions of the tested 5-HT4 receptor agonists. 5. The present results show that part of the voltage-activated K+ current in mouse colliculi neurones is cyclic AMP-sensitive and the blockade of the current by 5-HT involves the 5-HT4 receptor subtype.The putative implication of 5-HT4 receptors in neuronal plasticity, via a blockade of K+ channels, is discussed.

Animals↗

PubMed1992

Regulation of neurotransmitter enzyme by quisqualate subtype glutamate receptors in cultured cerebellar and hippocampal neurons.

The possible involvement of ionotropic and metabotropic quisqualate (QA) receptors in neuronal plasticity was studied in cultured glutamatergic cerebellar or hippocampal cells in terms of the specific activity of phosphate-activated glutaminase, an enzyme important in the synthesis of the putative neurotransmitter pool of glutamate. When cerebellar or hippocampal neurons were treated with QA, it elevated the specific activity of glutaminase in a dose-dependent manner. The half-maximal effect was obtained at about 0.1 microM, the maximum increase was at about 1 microM, but levels higher than 10 microM QA produced progressive reduction in glutaminase activity. In contrast, QA had little effects on the activities of lactate dehydrogenase and aspartate aminotransferase and the amount of protein, indicating that the increase in glutaminase was relatively specific. The QA-mediated increase in glutaminase was mimicked by the ionotropic QA receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; EC50, about 0.5 microM), but not by the metabotropic QA receptor agonist trans-(+-)-1-amino-cyclopentyl-1,3,dicarboxylate (t-ACPD; up to 0.5 mM). The specific ionotropic QA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) inhibited QA- and AMPA-mediated increases in glutaminase activity in a dose-dependent manner, whereas other glutamate receptor antagonists, D,L-2-amino-5-phosphonovalerate, gamma-D-glutamyl aminomethyl sulphonic acid and gamma-D-glutamyl diethyl ester were ineffective. The elevation of neurotransmitter enzyme was Ca(2+)-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Higher seizure susceptibility and enhanced tyrosine phosphorylation of N-methyl-D-aspartate receptor subunit 2B in fyn transgenic mice.

Earlier work has suggested that Fyn tyrosine kinase plays an important role in synaptic plasticity. To understand the downstream targets of Fyn signaling cascade in neurons, we generated transgenic mice expressing either a constitutively activated form of Fyn or native Fyn in neurons of the forebrain. Transgenic mice expressing mutant Fyn exhibited higher seizure activity and were prone to sudden death. Mice overexpressing native Fyn did not show such an obvious epileptic phenotype, but they exhibited accelerated kindling in response to once-daily stimulation of the amygdala. Tyrosine phosphorylation of at least three proteins was enhanced in the forebrains of both native and mutant fyn transgenic mice; tyrosine phosphorylation of these three proteins was reduced in fyn knockout mice, suggesting that they are substrates of Fyn. One of these proteins was identified as the subunit 2B (NR2B) of the N-methyl-D-aspartate (NMDA) receptor. Administration of MK-801, a noncompetitive NMDA receptor antagonist, retarded kindling in mice overexpressing native Fyn, as well as wild-type mice, suggests that the accelerated kindling in mice overexpressing Fyn is also mediated by the NMDA receptor activity. Our results thus suggest that tyrosine phosphorylation by Fyn might be involved in regulation of the susceptibility of kindling, one form of the NMDA receptor-mediated neuronal plasticity.

Amino Acid Sequence↗

PubMed2003

CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X protein.

Neuronal plasticity requires actin cytoskeleton remodeling and local protein translation in response to extracellular signals. Rho GTPase pathways control actin reorganization, while the fragile X mental retardation protein (FMRP) regulates the synthesis of specific proteins. Mutations affecting either pathway produce neuronal connectivity defects in model organisms and mental retardation in humans. We show that CYFIP, the fly ortholog of vertebrate FMRP interactors CYFIP1 and CYFIP2, is specifically expressed in the nervous system. CYFIP mutations affect axons and synapses, much like mutations in dFMR1 (the Drosophila FMR1 ortholog) and in Rho GTPase dRac1. CYFIP interacts biochemically and genetically with dFMR1 and dRac1. Finally, CYFIP acts as a dRac1 effector that antagonizes FMR1 function, providing a bridge between signal-dependent cytoskeleton remodeling and translation.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Reversible, activity-dependent targeting of profilin to neuronal nuclei.

The actin cytoskeleton in pyramidal neurons plays a major role in activity-dependent processes underlying neuronal plasticity. The small actin-binding protein profilin shows NMDA receptor-dependent accumulation in dendritic spines, which is correlated with suppression of actin dynamics and long-term stabilization of synaptic morphology. Here we show that following NMDA receptor activation profilin also accumulates in the nucleus of hippocampal neurons via a process involving rearrangement of the actin cytoskeleton. This simultaneous targeting to dendritic spines and the cell nucleus suggests a novel mechanism of neuronal plasticity in which profilin both tags activated synapses and influences nuclear events.

Actins↗

PubMed1997

Differential expression of microtubule-associated protein 1B phosphorylated isoforms in the adult rat nervous system.

Phosphorylated microtubule-associated protein 1B isoforms are thought to be involved in the plastic events taking place in neurons during development. However, little is known about their expression and possible role in the mature nervous system. To gain insight into the mechanisms underlying neuronal plasticity in the adult, we studied the pattern of expression of three microtubule-associated protein 1B isoforms in the entire adult rat nervous system. Accordingly, we performed western blots and immunohistochemistries using the antibodies 125, 150 and 531, which specifically recognize phosphorylated and unphosphorylated microtubule-associated protein 1B epitopes. Two electrophoretically distinct microtubule-associated protein 1B isoforms, slow-migrating and fast-migrating, were detected with the antibodies. The pattern of expression of these isoforms in the adult rat nervous system was region specific. Phosphorylated slow-migrating microtubule-associated protein 1B was expressed at all cellular compartments of primary sensory neurons in the central and peripheral nervous systems. In addition to primary sensory axons, slow-migrating microtubule-associated protein 1B was encountered at some other axons within the central nervous system. We discuss the correlation between slow-migrating microtubule-associated protein 1B axonal content and the regenerative potential of neurons. Phosphorylated fast-migrating microtubule-associated protein 1B was exclusively found in central nervous system dendrites where synaptic plasticity with morphological changes occurs in the adult. Unphosphorylated fast-migrating microtubule-associated protein 1B was the only isoform present in the bodies and dendrites of all motor neurons, and in peripheral and central nervous system glial cells of myelinated tracts with slow-migrating microtubule-associated protein 1B-containing axons. In summary, this report describes the pattern of expression of microtubule-associated protein 1B isoforms in the entire adult rat nervous system. In addition, it provides some information about the possible functional implications of phosphorylated microtubule-associated protein 1B isoforms in the adult.

Animals↗

PubMed2001

Brain-derived neurotrophic factor enhances depolarization-evoked glutamate release in cultured cortical neurons.

Brain-derived neurotrophic factor (BDNF) has been reported to play an important role in neuronal plasticity. In this study, we examined the effect of BDNF on an activity-dependent synaptic function in an acute phase. First, we found that short-term treatment (10 min) with BDNF enhanced depolarization-evoked glutamate release in cultured cortical neurons. The enhancement diminished gradually according to the length of BDNF treatment. The BDNF-enhanced release did not require the synthesis of protein and mRNA. Both tetanus toxin and bafilomycin abolished the depolarization-evoked glutamate release with or without BDNF, indicating that BDNF acted via an exocytotic pathway. Next, we investigated the effect of BDNF on intracellular Ca(2+). BDNF potentiated the increase in intracellular Ca(2+) induced by depolarization. The Ca(2+) was derived from intracellular stores, because thapsigargin completely inhibited the potentiation. Furthermore, both thapsigargin and xestospongin C inhibited the effect of BDNF. These results suggested that the release of Ca(2+) from intracellular stores mediated by the IP(3) receptor was involved in the BDNF-enhanced glutamate release. Last, it was revealed that the enhancement of glutamate release by BDNF was dependent on the TrkB-PLC-gamma pathway. These results clearly demonstrate that short-term treatment with BDNF enhances an exocytotic pathway by potentiating the accumulation of intracellular Ca(2+) through intracellular stores.

Animals↗

PubMed1992

Pain-related increases in spinal cord membrane-bound protein kinase C following peripheral nerve injury.

Neuropathic pain following nerve injury is thought to involve central nervous system Ca(2+)-mediated neuronal plastic changes. This study provides evidence that induction and/or maintenance of post-injury neuropathic pain behaviors in the rat is associated with increases in membrane-bound protein kinase C (PKC), a Ca(2+)-dependent process known to mediate central nervous system neuronal plasticity. In addition, spinal cord administration of GM1 ganglioside, an intracellular inhibitor of PKC translocation/activation, reverses both increased levels of membrane-bound PKC and pain-related behaviors. Thus, persistent post-injury neuropathic pain may be mediated by the initiation of excitatory neuropathological processes resulting from an increase in membrane-bound PKC.

Animals↗

PubMed2001

Beta -amyloid-(1-42) impairs activity-dependent cAMP-response element-binding protein signaling in neurons at concentrations in which cell survival Is not compromised.

Cognitive impairment is a major feature of Alzheimer's disease and is accompanied by beta-amyloid (Abeta) deposition. Transgenic animal models that overexpress Abeta exhibit learning and memory impairments, but neuronal degeneration is not a consistent characteristic. We report that levels of Abeta-(1-42), which do not compromise the survival of cortical neurons, may indeed interfere with functions critical for neuronal plasticity. Pretreatment with Abeta-(1-42), at sublethal concentrations, resulted in a suppression of cAMP-response element-binding protein (CREB) phosphorylation, induced by exposure to either 30 mm KCl or 10 microm N-methyl-d-aspartate. The effects of Abeta-(1-42) seem to involve mechanisms unrelated to degenerative changes, since Abeta-(25-35), a toxic fragment of Abeta, at sublethal concentrations did not interfere with activity-dependent CREB phosphorylation. Furthermore, caspase inhibitors failed to counteract the Abeta-(1-42)-evoked suppression of CREB activation. Abeta-(1-42) also interfered with events downstream of activated CREB. The Abeta-(1-42) treatment suppressed the activation of the cAMP response element-containing brain-derived neurotrophic factor (BDNF) exon III promoter and the expression of BDNF exon IIII mRNA induced by neuronal depolarization. In view of the critical role of CREB and BDNF in neuronal plasticity, including learning and memory, the observations indicate a novel pathway through which Abeta may interfere with neuronal functions and contribute to cognitive deficit in Alzheimer's disease before the stage of massive neuronal degeneration.

Amino Acid Chloromethyl Ketones↗

PubMed2005

Phosphodiesterase 4B (PDE4B) and cAMP-level regulation within different tissue fractions of rat hippocampal slices during long-term potentiation in vitro.

Molecular events associated with mnemonic processes and neuronal plasticity are postulated to result in functional changes in synaptic structure. One possible site is the post-synaptic density, where activity-dependent changes modulate signal transduction cascades. In this report, we detail spatial-temporal changes for phosphodiesterase 4B (PDE4B) proteins and their substrate cAMP within three neuronal fractions during early and late long-term potentiation (LTP). The cAMP-dependent protein kinase A cascade--which can be regulated by distinct PDE4B activity--is required for mnemonic processes as well as mechanisms of neuronal plasticity, such as those during the maintenance or late-LTP. Fluorescence in situ hybridization studies (FISH) identified no translocation of PDE4B3 from the soma after late-LTP induction indicating a subtle, local control of PDE4B activity. Protein changes were detected within the PSD-enriched fraction. From these results, we conclude that either the changes in PDE4B are due to modulation of pre-existing mRNA, or that the protein is specifically translocated to activated synaptic structures. Furthermore, we report late changes in cAMP levels in the somato-dendritic fraction and discuss this result with the increased PDE4B1/3 doublet in the PSD-enriched fraction.

3',5'-Cyclic-AMP Phosphodiesterases↗