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At least 235 records · Page 13Linked to original sources
PubMed2003

Transmitter modulation of slow, activity-dependent alterations in sodium channel availability endows neurons with a novel form of cellular plasticity.

Voltage-gated Na+ channels are major targets of G protein-coupled receptor (GPCR)-initiated signaling cascades. These cascades act principally through protein kinase-mediated phosphorylation of the channel alpha subunit. Phosphorylation reduces Na+ channel availability in most instances without producing major alterations of fast channel gating. The nature of this change in availability is poorly understood. The results described here show that both GPCR- and protein kinase-dependent reductions in Na+ channel availability are mediated by a slow, voltage-dependent process with striking similarity to slow inactivation, an intrinsic gating mechanism of Na+ channels. This process is strictly associated with neuronal activity and develops over seconds, endowing neurons with a novel form of cellular plasticity shaping synaptic integration, dendritic electrogenesis, and repetitive discharge.

Animals↗
PubMed2001

Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory.

Calcineurin is a calcium-dependent protein phosphatase that has been implicated in various aspects of synaptic plasticity. By using conditional gene-targeting techniques, we created mice in which calcineurin activity is disrupted specifically in the adult forebrain. At hippocampal Schaffer collateral-CA1 synapses, LTD was significantly diminished, and there was a significant shift in the LTD/LTP modification threshold in mutant mice. Strikingly, although performance was normal in hippocampus-dependent reference memory tasks, including contextual fear conditioning and the Morris water maze, the mutant mice were impaired in hippocampus-dependent working and episodic-like memory tasks, including the delayed matching-to-place task and the radial maze task. Our results define a critical role for calcineurin in bidirectional synaptic plasticity and suggest a novel mechanistic distinction between working/episodic-like memory and reference memory.

Animals↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2003

Rapid motor learning in the translational vestibulo-ocular reflex.

Motor learning was induced in the translational vestibulo-ocular reflex (TVOR) when monkeys were repeatedly subjected to a brief (0.5 sec) head translation while they tried to maintain binocular fixation on a visual target for juice rewards. If the target was world-fixed, the initial eye speed of the TVOR gradually increased; if the target was head-fixed, the initial eye speed of the TVOR gradually decreased. The rate of learning acquisition was very rapid, with a time constant of approximately 100 trials, which was equivalent to <1 min of accumulated stimulation. These learned changes were consolidated over >or=1 d without any reinforcement, indicating induction of long-term synaptic plasticity. Although the learning generalized to targets with different viewing distances and to head translations with different accelerations, it was highly specific for the particular combination of head motion and evoked eye movement associated with the training. For example, it was specific to the modality of the stimulus (translation vs rotation) and the direction of the evoked eye movement in the training. Furthermore, when one eye was aligned with the heading direction so that it remained motionless during training, learning was not expressed in this eye, but only in the other nonaligned eye. These specificities show that the learning sites are neither in the sensory nor the motor limb of the reflex but in the sensory-motor transformation stage of the reflex. The dependence of the learning on both head motion and evoked eye movement suggests that Hebbian learning may be one of the underlying cellular mechanisms.

Animals↗
PubMed2005

Ethanol alters trafficking and functional N-methyl-D-aspartate receptor NR2 subunit ratio via H-Ras.

The N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic plasticity and is one of the main targets for alcohol (ethanol) in the brain. Trafficking of the NMDAR is emerging as a key regulatory mechanism that underlies channel activity and synaptic plasticity. Here we show that exposure of hippocampal neurons to ethanol increases the internalization of the NR2A but not NR2B subunit of the NMDAR via the endocytic pathway. We further observed that ethanol exposure results in NR2A endocytosis through the activation of H-Ras and the inhibition of the tyrosine kinase Src. Importantly, ethanol treatment alters functional subunit composition from NR2A/NR2B- to mainly NR2B-containing NMDARs. Our results suggest that addictive drugs such as ethanol alter NMDAR trafficking and subunit composition. This may be an important mechanism by which ethanol exerts its effects on NMDARs to produce alcohol-induced aberrant plasticity.

Adaptor Protein Complex 2↗
PubMed2002

A dominant negative Egr inhibitor blocks nerve growth factor-induced neurite outgrowth by suppressing c-Jun activation: role of an Egr/c-Jun complex.

Members of the Egr family of transcription factors are rapidly and robustly induced by neurotransmitters and neurotrophins and have been implicated in mediating enduring changes in neuronal function elicited by these stimuli. Because we have found in previous studies that a dominant negative inhibitor of Egr action, the Egr zinc finger domain (ZnEgr), blocks NGF-induced neurite outgrowth in PC12 cells, we have used this preparation to help identify the downstream targets of Egr proteins involved in plasticity. Our investigation into the mechanism of action of ZnEgr indicates that it blocks NGF-induced neurite outgrowth by suppressing activation of c-Jun, a critical step in the signaling pathway mediating this response. Although we had assumed that ZnEgr exerts its effects by binding to the Egr response element (ERE) and thereby blocking target gene regulation by Egr proteins, this classical mode of action appears to be too slow to mediate the effects of Egr proteins on c-Jun activation. In evaluating alternative ERE-independent mechanisms of Egr (and ZnEgr) action, we found that Egr1 and c-Jun coprecipitate and that ZnEgr disrupts formation of the Egr1/c-Jun complex. Furthermore, mutations of ZnEgr that greatly impair or abolish its ability to bind to the ERE do not block its ability to suppress c-Jun activation or neurite outgrowth induced by NGF. Accordingly, our studies indicate that Egr and ZnEgr proteins regulate c-Jun activation via a novel mechanism, protein-protein interaction with c-Jun, rather than via their classical mode of action, binding to the ERE.

Cell Line↗
PubMed2006

Activating Notch1 mutations are an early event in T-cell malignancy of Ikaros point mutant Plastic/+ mice.

Ikaros and Notch1 genes are critical to T-cell differentiation through transcriptional activation of target genes and interaction with chromatin remodeling complexes. An Ikaros (Plastic) point mutation inhibits activity of normal Ikaros and Ikaros family members, and leads to T-cell lymphoma in heterozygotes (Plstc/+). Analysis revealed Notch1 activating mutations in 12 of 17 Plstc/+ lymphomas (70%), analogous to those in human T-ALL. Mice acquired Notch1 mutations in lymph nodes as early as 7 weeks. Thus, combined Notch1 and Ikaros dysfunction can be a significant early event in T-cell proliferation and tumorigenesis.

Animals↗
PubMed2000

Analysis of spine morphological plasticity in developing hippocampal pyramidal neurons.

Dendritic spines are targets of most excitatory inputs in the central nervous system (CNS) and are morphologically heterogeneous. Ultrastructural studies have traditionally classified spines into four major categories (filopodia, stubby, thin, and mushroom) based on their distinct morphologies. The recent discovery of rapid morphological plasticity of spines has raised the possibility that those categories, rather than being intrinsically different populations of spines, represent instead temporal snapshots of a single dynamic phenomenon. We examined this question with two-photon time-lapse imaging of developing hippocampal pyramidal neurons, transfected with E-GFP in cultured slices. After blind scoring to morphologically classify spines into the four traditional groups, we analyzed the fate of populations of spines over a period of 2-4 h. We found considerable morphological conversions among all categories, although systematic trends were detected. While most stubbies and spines (defined for our analysis as the combination of thin and mushroom protrusions) retained their basic morphologies, most filopodia transformed into stubbies and spines, although they could also extend out of existing spines. Our results suggest that in developing hippocampal pyramidal neurons, traditional morphological distinctions are stable over short (<4 h) periods of time, but that at the same time, considerable mixing among these groups takes place.

Animals↗
PubMed1987

The cAMP cascade in the nervous system: molecular sites of action and possible relevance to neuronal plasticity.

Many intercellular messages regulate the activity of their target cells by altering the intracellular level of cAMP and, as a consequence, the phosphorylation state of proteins which serve as substrates for cAMP-dependent protein kinase. Such regulation plays a crucial role in neuronal development, neuronal function, and neuronal plasticity (e.g., elementary learning mechanisms). Ample information has been accumulated in recent years on the enzymes that regulate the level of cAMP or respond to it, on the regulation of cAMP synthesis by neurohormones, neurotransmitters, ions, and toxins, on neuronal-specific substrate proteins that are phosphorylated by the cAMP-dependent kinase, and on the interaction of the cAMP-cascade with other second-messenger systems within neurons. Such data, obtained by a combination of molecular-biological, biochemical, and cellular approaches, shed light on the detailed mechanisms by which modulation of a ubiquitous molecular cascade leads to a great variety of short-term as well as long-term specific neuronal responses and alterations.

Animals↗
PubMed2006

Deafferentation induces novel axonal projections in the auditory brainstem after hearing onset.

Deafferentation of neural tissue can result in cell death, morphological changes, and/or alterations in sources of innervation. These changes often occur during a limited period of development. In the auditory brainstem, the ventral cochlear nucleus (VCN) projects to the contralateral but not ipsilateral medial nucleus of the trapezoid body (MNTB). This pathway is part of a circuit that computes interaural intensity differences used in sound localization. Previous studies have shown that, after the cochlea is removed early in postnatal development, cells in the VCN on the deafferented side die, and the intact VCN innervates MNTB on both sides of the brain. These changes after cochlea removal are limited to an early postnatal period that preceeds hearing onset. In this study, we lesioned the VCN directly to evaluate plasticity in axonal pathways after hearing onset. We found that novel projections from the intact VCN to ipsilateral MNTB emerge after lesions performed as late as postnatal day 25. The morphological sequence of events is similar to that seen during the initial development of this pathway. These data suggest that plasticity in the auditory brainstem is possible when pathways are challenged with denervation of target nuclei. The results show that the opportunity for plasticity in auditory brainstem circuitry is more prolonged than previously thought and that novel pathways can form after the normal pathways are fully mature and functional. Moreover, sensitive periods for changes in individual pathways are independently regulated.

Aging↗
PubMed2005

Pharmacogenetics of the serotonin transporter.

Response to psychopharmacologic drugs is genetically complex, results from an interplay of multiple genomic variations with environmental influences, and depends on the structure or functional expression of gene products, which are direct drug targets or indirectly modify the development and synaptic plasticity of neural networks critically involved in their effects. During brain development, the serotonin (5HT) system, which is commonly targeted by antidepressant, anxiolytic, and antipsychotic drugs, controls neuronal specification, differentiation, and phenotype maintenance. While formation and integration of these neural networks is dependent on the action of multiple proteins, converging lines of evidence indicate that genetically controlled variability in the expression of the 5HT transporter (5HTT) is critical to the development and plasticity of distinct neurocircuits. The most promising finding to date indicate an association between the response time as well as overall response to serotonin reuptake inhibitors (SSRIs) and a common polymorphism (5HTTLPR) within the transcriptional control region of the 5HTT gene (SLC6A4) in patients with depressive disorders. The formation and maturation of serotonergic and associated systems, in turn, are influencing the efficacy of serotonergic compounds in a variety of psychiatric conditions. Based on the notion that complex gene x gene and gene x environment interactions in the regulation of brain plasticity are presumed to contribute to individual differences in psychopharmacologic drug response, the concept of developmental psychopharmacogenetics is emerging.

Animals↗
PubMed2000

Undermining the Baldwin expediting effect: does phenotypic plasticity accelerate evolution?

The claim that phenotypic plasticity speeds up evolution towards a target phenotype is a recent incarnation of the Baldwin effect. To differentiate this theory from earlier interpretations of Baldwin's ideas, we name it the Baldwin expediting effect. Models that demonstrate this effect assume an extreme fitness scenario which bestows high fitness upon a single optimal phenotype and treats all other phenotypes as equal. In two modeling frameworks, we demonstrate that the effects of plasticity on the rate of evolution are highly dependent on the fitness function and population starting conditions. We argue that phenotypic plasticity does not universally facilitate evolution. Furthermore, in cases where the Baldwin expediting effect occurs, it is not necessarily correlated with increased fitness and therefore is not sufficient to explain the evolutionary success of plasticity.

Biological Evolution↗
PubMed2003

Targeting the CREB pathway for memory enhancers.

Today, the clinical notion of 'memory disorder' is largely synonymous with 'Alzheimer's disease.' Only 50% of all dementias are of the Alzheimer's type though, and dementias represent only the more severe of all learning/memory disorders that derive from heredity, disease, injury or age. Perhaps as many as 30 million Americans suffer some type of clinically recognized memory disorder. To date, therapeutic drugs of only one class have been approved for the treatment of Alzheimer's disease. Fortunately, basic research during the past 25 years has begun to define a 'chemistry of brain plasticity,' which is suggesting new gene targets for the discovery of memory enhancers.

Alzheimer Disease↗
PubMed2004

Pineal attrition, loss of cognitive plasticity, and onset of puberty during the teen years: is it a modern maladaptation exposed by evolutionary displacement?

Cognitive plasticity, a developmental trait that promotes acquisition of complex skills such as language or playing musical instruments, diminishes substantially during puberty. The loss of plasticity has been attributed to surge of sex steroids during adolescence, but the phenomenon remains poorly understood. We hypothesize that pineal involution during puberty may contribute to plasticity decay. The pineal gland produces melatonin, the level of which declines dramatically during onset of puberty. Emerging evidence suggest that melatonin may modulate cognitive plasticity, independent of the effects of sex steroids, and low sex steroids and high melatonin may be simultaneously required to maintain cognitive plasticity. Potential mechanisms by which melatonin may modulate plasticity are examined within the sleep and hippocampal long-term potentiation frameworks. Implications for psychiatric conditions that involve sleep disorders and learning dysfunctions such as schizophrenia and autism are discussed, and the potential adaptive roles of postprandial and postcoital sleep are explored. From the Darwinian perspective, development and reproductive maturity may represent distinct phases that require tailored cognitive strategies to maximize fitness. While cognitive flexibility and susceptibility to new skills may be paramount during development, reduced cognitive flexibility and increased cognitive determinism may enable more efficient responses to stimuli during adulthood. Thus, cognitive plasticity and cognitive determinism may represent trade-off adaptations and different dimensions of intelligence. The decline of plasticity and emergence of puberty during the second decade may be relics of prehistoric times when the human lifespan was short and the environment was relatively simple and static. Today, when the environment is more complex and dynamic, and humans are living far longer, the early obsolescence of plasticity during puberty may represent a Darwinian inefficiency exposed by evolutionary displacement. Regulation of plasticity may be a systemic phenomenon, as exemplified by the association of learning disability with allergic conditions, a form of immune plasticity dysfunction. Ramifications for other plastic functions that decline during puberty such as wound healing and hyaline cartilage regeneration are explored. Like the plasticity of immunity and cognition, the plasticity of hyaline cartilage during youth may enable hosts to respond to ecologic opportunities and generate the optimally adapted adult phenotype. Pineal involution may represent a potential target for therapeutic extension or restoration of plasticity after puberty. Extending plasticity may have far-reaching consequences for human evolution.

Adolescent↗
PubMed2005

Molecular dynamics studies on free and bound targets of the bovine papillomavirus type I e2 protein: the protein binding effect on DNA and the recognition mechanism.

Molecular dynamics simulations of a total duration of 30 ns in explicit solvent were carried out on the BPV-1-E2 protein complexed to a high-affinity DNA target containing the two hydrogen-bonded ACCG.CGGT half-sites separated by the noncontacted ACGT sequence. The analysis of the trajectories focuses on the DNA structure and on the dynamics. The data are compared to those issued from recent simulations made on three free targets that recognize E2 with different affinities. E2 does not drastically perturb the mechanic properties of the free DNA: the structural relationships between the BI/BII backbone substates and some helical parameters are preserved in the complex despite a severe slowing down of the phosphate group motions. The structures of both free and bound half-sites are very close to each other although the conformational space explored by these regions is narrowed when they are contacted by the protein. The enhanced plasticity found in the best free target spacers, mainly manifested through the backbone motions, allows a clear overlap between several free and bound global DNA features such as the base displacement. Furthermore, this flexibility is preserved in the complex. Our results support the hypothesis that E2 takes advantage of free predistorted structures that may minimize the DNA deformation cost. In addition, we observe that E2 is far from totally stiffening the DNA, suggesting that the entropic penalty inherent in the complex formation could be limited.

Base Sequence↗
PubMed1999

Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning.

Gene-targeted mice lacking the L-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit GluR-A exhibited normal development, life expectancy, and fine structure of neuronal dendrites and synapses. In hippocampal CA1 pyramidal neurons, GluR-A-/- mice showed a reduction in functional AMPA receptors, with the remaining receptors preferentially targeted to synapses. Thus, the CA1 soma-patch currents were strongly reduced, but glutamatergic synaptic currents were unaltered; and evoked dendritic and spinous Ca2+ transients, Ca2+-dependent gene activation, and hippocampal field potentials were as in the wild type. In adult GluR-A-/- mice, associative long-term potentiation (LTP) was absent in CA3 to CA1 synapses, but spatial learning in the water maze was not impaired. The results suggest that CA1 hippocampal LTP is controlled by the number or subunit composition of AMPA receptors and show a dichotomy between LTP in CA1 and acquisition of spatial memory.

Action Potentials↗
PubMed2026

MicroRNAs and predicted targets in the switch from monolayered to spheroids of cholangiocarcinoma cells.

BACKGROUND: Extrahepatic cholangiocarcinoma (eCCA) is characterized by marked molecular heterogeneity and limited therapeutic options. MicroRNAs (miRNAs) are key post-transcriptional regulators of cancer-related pathways, but their contribution to tumor adaptation in physiologically relevant models remains poorly understood. Three-dimensional (3D) tumor spheroids better mimic in vivo conditions than conventional two-dimensional (2D) cultures. METHODS: We compared miRNA expression profiles in two eCCA cell lines (Sk-ChA-1 and Mz-ChA-1) grown as monolayers (2D) or multicellular tumor spheroids (3D). MiRNA profiling was performed using NanoString technology. Predicted targets were analyzed by over-representation analysis, and selected miRNAs and genes were validated by RT-qPCR and ELISA-based assays. RESULTS: 3D growth induced extensive miRNA remodeling, with distinct (54 deregulated in Sk-ChA-1 and 29 in Mz-ChA-1 cells) and partially overlapping signatures (miR-1283, miR-577, and miR-2113). Among the shared miRNAs, predicted targets included DUSP10 and RBFOX1, while in spheroids, cell-specific multiple miRNAs converged on shared targets (TNRC6B, SMARCAD1, ATG14, HMGA2, and CLOCK) displaying inverse expression patterns. The transcriptional program impacted MAPK signaling, enhanced EMT, and activated stress-adaptive networks but attenuated proliferation in 3D Sk-ChA-1 cells, while Mz-ChA-1 cells retained a more epithelial and proliferative profile. In this context, we point out the involvement of miR-19b-3p using anti-miR transfection experiments. CONCLUSION: Our findings reveal a miRNA-driven regulatory landscape associated with 3D growth in eCCA, linking tumor architecture to signaling rewiring and cellular plasticity, and highlight potentially druggable candidate targets and pathways to investigate as candidates using inhibitors or gene therapy-based interventions.

Humans↗
PubMed2002

Acute cholinergic rescue of synaptic plasticity in the neurodegenerating cortex of anti-nerve-growth-factor mice.

Deficits in cholinergic systems innervating cerebral cortex are associated with cognitive impairment during senescence and in age-related neurodegenerative pathologies. However, little is known about the role of cholinergic pathways in modulating cortical plasticity. Basal forebrain cholinergic neurons are a major target for nerve-growth factor (NGF). In order to investigate the relationship between cholinergic innervation and cortical synaptic plasticity, we exploited a transgenic mouse model in which the activity of NGF in the adult nervous system is neutralized by the expression of blocking antibodies to NGF itself (anti-NGF mice) [Ruberti, F. et al. (2000). J. Neurosci. 20, 2589-2601]. In 6-month-old anti-NGF mice, we show that the reduction in cholinergic innervation of the cortex is associated with different forms of synaptic plasticity impairment. A local, acute increase in the availability of acetylcholine rescues these synaptic plasticity deficits, thus indicating that a cholinergic system mediates the impairment of cortical plasticity at this early stage of the neurodegenerative process triggered by NGF neutralization. Our results represent an important step in unveiling the pivotal role of cholinergic transmission in modulating adult cortical plasticity.

Acetylcholine↗