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At least 1,009 records · Page 56Linked to original sources
PubMed2006

One-step immobilization of poly(dT)-modified DNA onto non-modified plastic substrates by UV irradiation for microarrays.

Previously, 'DNattach', an alternative DNA immobilization system for attaching modified oligonucleotide probes onto a gold surface by UV irradiation that can be used in various DNA microarray applications including gene expression analysis, was developed. Attached to the gold surface, the modified probes have been shown to successfully detect synaptogenesis in the developing mouse cerebellum. In this study, this technology to immobilize modified oligonucleotide probes onto three different non-modified plastic surfaces in a microarray format has been further expanded. Using this system, single nucleotide polymorphism (SNP) genotyping of both oligonucleotide and PCR product targets has been successfully performed and it has also been shown that the probes immobilized on the slides can be used efficiently in hybridization experiments. Furthermore, it has been shown that probe concentrations of only 1-5 microM are sufficient for hybridization and that this immobilization method provides hybridization signals greater than those of conventional immobilization techniques.

Nucleic Acid Hybridization↗
PubMed1999

Ultrastructural localization of full-length trkB immunoreactivity in rat hippocampus suggests multiple roles in modulating activity-dependent synaptic plasticity.

Neurotrophins acting at the trkB receptor have been shown to be important modulators of activity-dependent plasticity in the hippocampus, but the mechanisms underlying these effects are not yet well understood. To identify the cellular and subcellular targets of trkB ligands in the adult rat hippocampal formation, full-length trkB receptor immunoreactivity (trkB-IR) was localized using electron microscopy. trkB-IR was present in the glutamatergic pyramidal and granule cells. Labeling in these neurons appeared as discrete clusters and was primarily in axons, excitatory-type axon terminals, and dendritic spines and to a lesser extent in somata and dendritic shafts. trkB-IR was commonly found on the plasma membrane of dendritic spines, whereas in other subcellular regions trkB-IR was often intracellular. Labeling was strikingly dense within axon initial segments, suggesting extensive receptor trafficking. trkB-IR was not confined to pyramidal and granule cells. Dense trkB-IR was found in occasional interneuron axon initial segments, some axon terminals forming inhibitory-type synapses onto somata and dendritic shafts, and excitatory-type terminals likely to originate extrahippocampally. This suggests that trkB is contained in some GABAergic interneurons, neuromodulatory (e.g., cholinergic, dopaminergic, and noradrenergic) afferents, and/or glutamatergic afferents. These data indicate that full-length trkB receptor activation may modulate glutamatergic pathways of the trisynaptic circuit both presynaptically at axon terminals and initial segments and postsynaptically at dendritic spines and shafts. Signaling via catalytic trkB may also presynaptically affect inhibitory and modulatory neurons. A pan-trkB antibody labeled the same neuronal populations as the full-length-specific trkB antiserum, but the labels differed in density at various subcellular sites. These findings provide an ultrastructural foundation for further examining the mechanisms through which neurotrophins acting at trkB receptors contribute to synaptic plasticity.

Amino Acid Sequence↗
PubMed2006

Multivariate neurocognitive and emotional profile of a mannosidosis murine model for therapy assessment.

alpha-Mannosidosis is a lysosomal storage disorder caused by lysosomal alpha-mannosidase (LAMAN) deficiency that leads to neurocognitive dysfunctions, psychotic symptoms and emotional changes in human patients. A murine mannosidosis model, LAMAN-deficient mice, was examined on a behavioral task battery that included test for neuromotor, exploratory and neurocognitive (spatial learning and memory) abilities, and multivariate statistical analyses were used to identify behavioral and neurocognitive domains that are most heavily affected by LAMAN deficiency. In addition, we further investigated synaptic plasticity recordings on hippocampal slices that may relate to these behavioral alterations. Correlation analysis revealed significant intra- and intertask correlations and factor analysis that included all 21 behavioral variables identified three main factors (exploration/emotionality, locomotion and learning/memory abilities). Significant correlations were observed between genotype, and factor 1 (exploration/emotionality) and factor 3 (learning/memory abilities). Discriminant function analysis showed that "path length in the open field test" and "time spent in the target quadrant during the water maze probe trial" were the most decisive variables to distinguish between the genotypes. We therefore suggest that these variables would be especially important in forthcoming therapy assessment experiments using this murine mannosidosis model. LAMAN-deficient mice displayed severe changes in synaptic plasticity, which may have contributed to the neurocognitive impairments observed. The present report further shows that targeted deletion of the LAMAN gene in mice mimics many aspects of human alpha-mannosidosis, and these data provide a basis for future therapeutic experiments.

Animals↗
PubMed2002

Syndecan-3-deficient mice exhibit enhanced LTP and impaired hippocampus-dependent memory.

Syndecan-3 (N-syndecan) is a transmembrane heparan sulfate proteoglycan expressed predominantly in the nervous system in a developmentally regulated manner. Syndecan-3 has been suggested to play a role in the development and plasticity of neuronal connections by linking extracellular signals to the regulation of the cytoskeleton. To study its physiological functions, we produced mice deficient in syndecan-3 by gene targeting. The mutant animals are healthy, are fertile, and have no apparent defects in the structure of the brain. We focused on characterizing the functions of the hippocampus, a brain area where expression of syndecan-3 is prominent in adults. Mice lacking syndecan-3 exhibited an enhanced level of long-term potentiation (LTP) in area CA1, while basal synaptic transmission and short-term plasticity were similar to those in wild-type animals. Further, the mutant mice were not responsive to the syndecan-3 ligand heparin-binding growth-associated molecule, which inhibits LTP in area CA1 in wild-type animals. Behavioral testing of the syndecan-3-deficient mice revealed impaired performance in tasks assessing hippocampal functioning. We suggest that syndecan-3 acts as an important modulator of synaptic plasticity that influences hippocampus-dependent memory.

Animals↗
PubMed2007

Translational regulation of neuronal electrical properties.

The nervous system has an in-built capability to adjust its responsiveness to excitation according to the history of electrical activity faced by the neurons embedded within its networks. This control over excitability represents a form of homeostasis and is exhibited at multiple stages in the flow of information from the genome to the expression and modification of protein products. Information on the nature of the homeostatic phenomenon at some of these stages is still limited and emerging. This article outlines the various stages at which such neuronal intrinsic plasticity has been observed and draws particular attention to the role of the translation repressor protein, Pumilio, as an important factor in the process. The study of this protein is providing insights into the regulation of neuronal excitability and offers an important research target with benefits to investigators in many areas of neuroscience.

Animals↗
PubMed2002

Contactin supports synaptic plasticity associated with hippocampal long-term depression but not potentiation.

BACKGROUND: Changes in synaptic efficacy are believed to mediate the processes of learning and memory formation. Accumulating evidence implicates cell adhesion molecules in activity-dependent synaptic modifications associated with long-term potentiation (LTP); however, there is no precedence for the selective role of this molecule class in long-term depression (LTD). The mechanisms that modulate these processes still remain unclear. RESULTS: We report a novel role for glycosylphosphatidyl inositol (GPI)-anchored contactin in hippocampal CA1 synaptic plasticity. Contactin selectively supports paired-pulse facilitation (PPF) and NMDA (N-methyl-D-aspartate) receptor-dependent LTD but is not required for synaptic morphology, basal transmission, or LTP. Molecular analyses indicate that contactin is essential for the membrane and synaptic targeting of the contactin-associated protein (Caspr/paranodin) and for the proper distribution of a presumptive ligand, receptor protein tyrosine phosphatase beta (RPTPbeta)/phosphacan. CONCLUSIONS: These results indicate that contactin plays a selective role in synaptic plasticity and identify PPF and LTD, but not LTP, as contactin-dependent processes. Engagement of the contactin-Caspr complex with RPTPbeta may thus regulate cell-cell interactions contributing to specific synaptic plasticity forms.

Animals↗
PubMed2003

Plasticity of feature-based selection in triple-conjunction search.

Two experiments examined the disruption of feature-based selection in triple-conjunction search at multiple target transfers. In Experiment 1, after 10 training sessions, a new target possessing previous distractor features was introduced. This produced disruption in RT and fixation number, but no disruption in feature-based selection. Specifically, there was a tendency to fixate objects sharing the target's contrast polarity and shape and this did not change even upon transfer to the new target. In Experiment 2, 30 training sessions were provided with three target transfers. At the first transfer, the results replicated Experiment 1. Subsequent transfers did not produce disruption on any measure. These findings are discussed in terms of strength theory, Guided Search, rule-based approaches to perceptual learning, and the area activation model.

Adult↗
PubMed2006

The effect of repetitive transcranial magnetic stimulation on dystonia: a clinical and pathophysiological approach.

Dystonia is characterized by sustained muscle contraction, which frequently causes repetitive, twisting movements or abnormal posture. The precise pathophysiological mechanisms of dystonia are still unknown. Several studies did demonstrate that, although motor cortex hyperexcitability appears to be responsible for abnormal co-contraction and overflow to adjacent muscles, plasticity mechanisms and integrative sensorimotor processing are also likely to be involved in this condition. Current dystonia treatments are based on oral medication, injection of botulinum toxin and, in a low proportion of cases, bi-pallidal deep brain stimulation. However, treatment outcome is generally disappointing. A few researchers have reported the application of repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex or the premotor cortex, with the goal of decreasing motor cortex hyperexcitability. This article reviews all studies using this technique in dystonia and discusses rTMS therapeutic impact and its possible mechanisms of action in this indication. Currently, the premotor cortex seems to be the best target for rTMS in dystonia. Rather than merely reducing the hyperexcitability of the primary motor cortex, this technique's clinical benefit seems to result from modifications in plasticity and restoration of sensorimotor integration. The corollary technique for chronic rTMS is electrical cortical stimulation. Even though this new therapeutic tool may have therapeutic promise, more studies are required to confirm it. In particular, we need to broaden our knowledge of rTMS impact on the various forms of dystonia and to optimize target localization.

Dystonia↗
PubMed2004

Validation of BacT/ALERT plastic culture bottles for use in testing of whole-blood-derived leukoreduced platelet-rich-plasma-derived platelets.

BACKGROUND: Bacterial detection of platelet (PLT)-rich-plasma (PRP)-derived PLTs presents unique challenges for countries that do not allow pooling before storage. This study validated the BacT/ALERT for use in testing pooled PRP-derived PLTs with nine contaminating organisms. STUDY DESIGN AND METHODS: Isolates of Bacillus cereus, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, Serratia marcescens, Streptococcus viridans, and Propionibacterium acnes were inoculated into two PRP-derived PLT pools (target, 10 and 100 colony-forming units [CFUs]/mL; actual recovered concentrations, 5 and 90 CFUs/mL). Four milliliters of each postbacterial inoculation sample was inoculated into both plastic aerobic and anaerobic bottles and 0.5 mL was plated onto blood agar. RESULTS: All organisms (excluding P. acnes) were detected in 8.2 to 22.0 and 7.6 to 20.3 hours (10 and 100 CFUs/mL, respectively) and the mean time to detection was 15.0 and 13.1 hours (10 and 100 CFUs/mL, respective). P. acnes was detected with the anaerobic bottles in a mean of 74.9 and 64.3 hours (10 and 100 CFUs/mL, respectively). With E. cloacae, E. coli, K. pneumoniae, S. marcescens, and S. viridans detection with the anaerobic bottles was faster or equivalent to the detection with the aerobic bottles. This was most notable with S. viridans where the anaerobic bottle was reactive on average 21.6 and 10.8 hours (10 and 100 CFUs/mL, respectively) faster than the aerobic bottle. CONCLUSIONS: This study validates the use of the BacT/ALERT system for the detection of bacteria in PRP-derived PLTs in a pooled format. Overall, the use of the BacT/ALERT system allowed the detection of pooled PRP-derived PLTs inoculated with nine bacteria at 10 and 100 CFUs per mL in 7.6 to 22.0 hours (excluding P. acnes).

Bacteria↗
PubMed2004

Developmentally regulated switch in alternatively spliced SNAP-25 isoforms alters facilitation of synaptic transmission.

Although the basic molecular components that promote regulated neurotransmitter release are well established, the contribution of these proteins as regulators of the plasticity of neurotransmission and refinement of synaptic connectivity during development is elaborated less fully. For example, during the period of synaptic growth and maturation in brain, the expression of synaptosomal protein 25 kDa (SNAP-25), a neuronal t-SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) essential for action potential-dependent neuroexocytosis, is altered through alternative splicing of pre-mRNA transcripts. We addressed the role of the two splice-variant isoforms of SNAP-25 with a targeted mouse mutation that impairs the shift from SNAP-25a to SNAP-25b. Most of these mutant mice die between 3 and 5 weeks of age, which coincides with the time when SNAP-25b expression normally reaches mature levels in brain and synapse formation is essentially completed. The altered expression of these SNAP-25 isoforms influences short-term synaptic function by affecting facilitation but not the initial probability of release. This suggests that mechanisms controlling alternative splicing between SNAP-25 isoforms contribute to a molecular switch important for survival that helps to guide the transition from immature to mature synaptic connections, as well as synapse regrowth and remodeling after neural injury.

Alternative Splicing↗
PubMed2005

Biological significance of c-erbB family oncogenes in head and neck cancer.

Squamous cell carcinoma of the head and neck (SCCHN) tends to run an aggressive course and the prognosis has remained virtually unchanged in recent decades. The development of novel therapeutic strategies to improve patient outcome centres on the biology of the disease, namely the pivotal c-erbB family of growth factor receptors. c-erbB1 (or epidermal growth factor receptor, EGFR), is key to the pathogenesis of SCCHN and plays a central role in a complex network of downstream integrated signalling pathways. EGFR overexpression, detected in up to 90% of SCCHN, correlates with an increased risk of locoregional tumour relapse following primary therapy and relative resistance to treatment. The biological sequelae of erbB receptor activation are not simply cell proliferation, but also inhibition of apoptosis, enhanced migration, invasion, angiogenesis and metastasis: the 'hallmarks of cancer' [1]. As EGFR overexpression is associated with a poor clinical outcome in SCCHN, this receptor is attractive as a therapeutic target and the successful development of targeted therapies represents a paradigm shift in the medical approach to head and neck cancer. However, the extensive cross talk between signalling pathways, the multiple molecular aberrations and genetic plasticity in SCCHN all contribute to inherent and acquired resistance to both conventional and novel therapies. Understanding the cancer cell biology, in particular the significance of co-expression of c-erbB (and other) receptors, and the cell survival stimuli from (for example) activation of the phosphoinositide 3-kinase (PI3-kinase) cascade is fundamental to overcome current limitations in biologically targeted therapies.

Animals↗
PubMed2003

Synaptopodin-deficient mice lack a spine apparatus and show deficits in synaptic plasticity.

The spine apparatus is a cellular organelle that is present in many dendritic spines of excitatory neurons in the mammalian forebrain. Despite its discovery >40 years ago, the function of the spine apparatus is still unknown although calcium buffering functions as well as roles in synaptic plasticity have been proposed. We have recently shown that the 100-kDa protein synaptopodin is associated with the spine apparatus. Here, we now report that mice homozygous for a targeted deletion of the synaptopodin gene completely lack spine apparatuses. Interestingly, this absence of the spine apparatus is accompanied by a reduction in hippocampal long-term potentiation (LTP) in the CA1 region of the hippocampus and by an impairment of spatial learning in the radial arm maze test. This genetic analysis points to a role of the spine apparatus in synaptic plasticity.

Animals↗
PubMed2001

Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics.

Mood disorders have traditionally been conceptualized as neurochemical disorders, but there is now evidence from a variety of sources demonstrating regional reductions in central nervous system (CNS) volume, as well as reductions in the numbers and/or sizes of glia and neurons in discrete brain areas. Although the precise cellular mechanisms underlying these morphometric changes remain to be fully elucidated, the data suggests that mood disorders are associated with impairments of structural plasticity and cellular resilience. Recent preclinical and clinical studies have shown that signaling pathways involved in regulating cell survival and cell death are long-term targets for the actions of antidepressants and mood stabilizers. Antidepressants, lithium, and valproate indirectly regulate a number of factors involved in cell survival pathways, including CREB, BDNF, Bcl-2, and MAP kinases, and may thus bring about some of their delayed long term beneficial effects via underappreciated neurotrophic effects. The future development of treatments that more directly target molecules involved in critical CNS cell survival and cell death pathways thus hold promise as novel, improved long-term treatments for mood disorders.

Animals↗
PubMed1999

Lithium and synaptic plasticity.

Lithium, a small cation, has been used in the treatment of bipolar disorders since its introduction in the 1950s by John Cade. Extensive research on the mechanism of action of lithium has revealed several possible targets. For some time, the most widely accepted action of lithium was its inhibitory effect on the synthesis of inositol, resulting in depletion of inositol with profound effects on neuronal signal transduction pathways. However, several studies show that some effects of lithium are not mediated through inositol depletion. Recent findings demonstrate that lithium directly inhibits, in a non-competitive fashion, the activity of glycogen synthase kinase (GSK)-3beta, a serine/threonine kinase highly expressed in the central nervous system. Interestingly, inhibition of GSK-3beta has been shown to regulate neuronal plasticity by inducing axonal remodelling and increasing the levels of synaptic proteins. These findings raise the possibility for developing new therapeutic approaches for the treatment of bipolar disorders.

Antimanic Agents↗
PubMed2000

Plasticity in the rat spinal cord seen in response to lesions to the motor cortex during development but not to lesions in maturity.

Motor cortical inputs and proprioreceptive muscle afferents largely target the same spinal cord region. This study explored the idea that during development the two inputs interact via an activity-dependent mechanism to produce mature patterns of innervation. In rats, the forelimb motor cortex was ablated unilaterally at either postnatal day 7 (P7), the beginning of corticospinal synaptogenesis in the cervical cord, or at P50. Comparisons were made with sham-operated animals. At P70, muscle afferents from the extensor digitorum communis muscle, contralateral to the lesion, were transganglionically labeled with cholera toxin B-subunit. Lower cervical spinal cord sections were immunostained for cholera toxin B, parvalbumin, and cJun. Our small lesions had no obvious effects upon forelimb function. However, developmental lesions, but not adult lesions, were shown to significantly increase the number of muscle afferent boutons present in the contralateral ventral horn, compared with sham-operated controls. Also, the ratio of parvalbumin-positive neurons contralateral/ipsilateral to the developmental lesion (but not adult lesions) was decreased and the ratio of cJun-positive motoneurons increased. Thus, an early motor cortex lesion resulted in retention of a proportion of muscle afferent synapses to the ventral horn that are known to be lost during normal development. Parvalbumin and cJun are markers of neuronal activity suggesting that spinal circuitry develops permanently altered activity patterns in response to an early cortical lesion, although this plasticity is lost in the mature animal.

Age Factors↗
PubMed1995

Long-term potentiation and synaptic protein phosphorylation.

Long-term potentiation (LTP) is a well known experimental model for studying the activity-dependent enhancement of synaptic plasticity, and because of its long duration and its associative properties, it has been proposed as a system to investigate the molecular mechanisms of memory formation. At present, there are several lines of evidence that indicate that pre- and postsynaptic kinases and their specific substrates are involved in molecular mechanisms underlying LTP. Many studies focus on the involvement of protein kinase C (PKC). One way to investigate the role of PKC in long-term potentiation is to determine the degree of phosphorylation of its substrates after in situ phosphorylation in hippocampal slices. Two possible targets are the presynaptic membrane-associated protein B-50 (a.k.a. GAP 43, neuromodulin and F1), which has been implicated in different forms of synaptical plasticity in the brain such as neurite outgrowth, hippocampal LTP and neurotransmitter release, and the postsynaptic protein neurogranin (a.k.a. RC3, BICKS and p17) which function remains to be determined. This review will focus on the protein kinase C activity in pre- and postsynaptic compartment during the early phase of LTP and the possible involvement of its substrates B-50 and neurogranin.

Animals↗
PubMed2003

Synaptic plasticity in rat subthalamic nucleus induced by high-frequency stimulation.

The technique of deep brain stimulation (DBS) has become a preferred surgical choice for the treatment of advanced Parkinson's disease. The subthalamic nucleus (STN) is presently the most promising target for such DBS. In this study, whole-cell patch-clamp recordings were made from 46 STN neurons in rat brain slices to examine the effect of high-frequency stimulation (HFS) of the STN on glutamatergic synaptic transmission in STN neurons. HFS, consisting of trains of stimuli at a frequency of 100 Hz for 1 min, produced three types of synaptic plasticity in 17 STN neurons. First, HFS of the STN induced short-term potentiation (STP) of evoked postsynaptic current (EPSC) amplitude in four neurons. STP was associated with a reduction in the EPSC paired-pulse ratio, suggesting a presynaptic site of action. Second, HFS of the STN generated long-term potentiation (LTP) of EPSC amplitude in eight neurons. Although the EPSC paired-pulse ratio was reduced transiently in the first 2 min following HFS, ratios measured 6-20 min after HFS were unchanged from control. This suggests that LTP is maintained by a postsynaptic mechanism. Third, HFS produced long-term depression (LTD) of EPSC amplitude in five STN neurons. LTD was associated with a significant increase in EPSC paired-pulse ratios, indicating a presynaptic site of action. These results suggest that HFS can produce long-term changes in the efficacy of synaptic transmission in the STN. HFS-induced synaptic plasticity might be one mechanism underlying the effectiveness of DBS in the STN as a treatment of advanced Parkinson's disease.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2007

Molecular imaging of angiogenesis.

Angiogenesis (the growth of new blood vessels) is a complex multistep process that involves multiple cell types, numerous growth factors, and complex regulatory checks and balances. Tight control of vascular remodeling evolved to ensure stability of the vasculature while maintaining the body's ability to rapidly mount an angiogenic response requiring a high degree of plasticity. Angiogenesis is critical not only for physiological development, but also for the progression of pathologies, and is thus a target for therapeutic intervention. The importance of the process coupled with the ease of access for delivery of contrast agents makes the vasculature at large, and angiogenesis in particular, a favorable target of functional and molecular imaging. Recent developments in molecular imaging tools have expanded our views to encompass many components of the process. Functional imaging of blood volume, vessel permeability, and vasoreactivity is complemented by novel contrast agents that reveal specific targets on endothelial cells. Methods have been developed to label vascular cells so as to track their recruitment to sites of angiogenesis, and new "smart" contrast agents have been designed to reveal the activity of enzymatic reactions in altering the extracellular matrix (ECM) during angiogenesis.

Angiogenesis Inducing Agents↗