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At least 1,189 records · Page 66Linked to original sources
PubMed1997

Inhibition of neuronal process outgrowth and neuronal specific gene activation by the Brn-3b transcription factor.

The differentiation of the ND7 neuronal cell line to a nondividing phenotype bearing numerous neurite processes is accompanied by a dramatic increase in the levels of the activating POU family transcription factor Brn-3a and a corresponding fall in the levels of the closely related inhibitory factor Brn-3b. We have previously shown that the artificial overexpression of Brn-3a in these cells can induce neurite outgrowth and the activation of genes encoding synaptic vesicle proteins in the absence of a differentiation-inducing stimulus. Here we show that overexpression of Brn-3b can reduce process outgrowth and synaptic vesicle gene expression following exposure to a stimulus which would normally induce differentiation. These inhibitory effects are abolished by altering a single amino acid in the POU homeodomain of Brn-3b to its equivalent in Brn-3a. The converse mutation in Brn-3a allows it to inhibit process outgrowth in response to a differentiation-inducing stimulus. Hence a single amino acid difference results in these closely related factors having opposite effects and allows the balance between them to regulate differentiation.

Animals↗
PubMed2003

Mitochondrial regulation of synaptic plasticity in the hippocampus.

Synaptic mechanisms of plasticity are calcium-dependent processes that are affected by dysfunction of mitochondrial calcium buffering. Recently, we observed that mice deficient in mitochondrial voltage-dependent anion channels, the outer component of the mitochondrial permeability transition pore, have impairments in learning and hippocampal synaptic plasticity, suggesting that the mitochondrial permeability transition pore is involved in hippocampal synaptic plasticity. In this study, we examined the effect on synaptic transmission and plasticity of blocking the permeability transition pore with low doses of cyclosporin A and found a deficit in synaptic plasticity and an increase in base-line synaptic transmission. Calcium imaging of presynaptic terminals revealed a transient increase in the resting calcium concentration immediately upon incubation with cyclosporin A that correlated with the changes in synaptic transmission and plasticity. The effect of cyclosporin A on presynaptic calcium was abolished when mitochondria were depolarized prior to cyclosporin A exposure, and the effects of cyclosporin A and mitochondrial depolarization on presynaptic resting calcium were similar, suggesting a mitochondrial locus of action of cyclosporin A. To further characterize the calcium dynamics of the mitochondrial permeability transition pore, we used an in vitro assay of calcium handling by isolated brain mitochondria. Cyclosporin A-exposed mitochondria buffered calcium more rapidly and subsequently triggered a more rapid mitochondrial depolarization. Similarly, mitochondria lacking the voltage-dependent anion channel 1 isoform depolarized more readily than littermate controls. The data suggest a role for the mitochondrial permeability transition pore and voltage-dependent anion channels in mitochondrial synaptic calcium buffering and in hippocampal synaptic plasticity.

Animals↗
PubMed2000

Inflated wings, tissue autolysis and early death in tissue inhibitor of metalloproteinases mutants of Drosophila.

In vertebrates, tissue inhibitors of metalloproteinases (TIMPs) play key roles in extracellular matrix (ECM) homeostasis and growth control. Deletion of the recently cloned Timp gene of Drosophila results in a subviable phenotype. Adult flies display inflated wings similar to integrin mutants, suffer from a bloated gut and progressive dissolution of internal tissues, and die prematurely. Our results demonstrate that the Timp gene product controls selective aspects of ECM function in Drosophila, and suggest that it is involved in cell adhesion/cell signaling pathways. Hence, Drosophila Timp mutants may prove useful as a model system for a wide variety of pathological conditions related to ECM dysregulation.

Abdomen↗
PubMed2003

Synapse formation is regulated by the signaling adaptor GIT1.

Dendritic spines in the central nervous system undergo rapid actin-based shape changes, making actin regulators potential modulators of spine morphology and synapse formation. Although several potential regulators and effectors for actin organization have been identified, the mechanisms by which these molecules assemble and localize are not understood. Here we show that the G protein-coupled receptor kinase-interacting protein (GIT)1 serves such a function by targeting actin regulators and locally modulating Rac activity at synapses. In cultured hippocampal neurons, GIT1 is enriched in both pre- and postsynaptic terminals and targeted to these sites by a novel domain. Disruption of the synaptic localization of GIT1 by a dominant-negative mutant results in numerous dendritic protrusions and a significant decrease in the number of synapses and normal mushroom-shaped spines. The phenotype results from mislocalized GIT1 and its binding partner PIX, an exchange factor for Rac. In addition, constitutively active Rac shows a phenotype similar to the GIT1 mutant, whereas dominant-negative Rac inhibits the dendritic protrusion formation induced by mislocalized GIT1. These results demonstrate a novel function for GIT1 as a key regulator of spine morphology and synapse formation and point to a potential mechanism by which mutations in Rho family signaling leads to decreased neuronal connectivity and cognitive defects in nonsyndromic mental retardation.

Actins↗
PubMed2004

Three exercise paradigms differentially improve sensory recovery after spinal cord contusion in rats.

Spinal cord injury (SCI) induces incapacitating neuropathic pain in the form of allodynia-a painful response to normally non-noxious stimuli. Unfortunately, the underlying mechanisms of these sensory changes are not well understood, and effective treatments for allodynia have proven elusive. We examined whether physical exercise can improve sensory function after experimental SCI by promoting neurotrophin expression in the spinal cord and periphery, which modulates synaptic transmission and function. Female rats with moderate spinal cord contusion participated in treadmill training, swim training, stand training or were untrained. Exercise training began 4 days post surgery, lasted 20-25 min per day, 5 days a week for 7 weeks. Allodynia, as measured using von Frey hairs of different bending forces to the plantar hind paw, developed in the untrained group 3 weeks after SCI. Treadmill training ameliorated allodynia and restored normal sensation by 5 weeks. Swim training had a transient beneficial effect, but allodynia returned by 7 weeks. Stand training had no effect. Resolution of allodynia after treadmill training was associated with normal mRNA levels of brain-derived neurotrophic factor (BDNF) in both the lumbar spinal cord and soleus muscle. No other exercise paradigm restored BDNF centrally and peripherally. Greater recovery from allodynia correlated significantly with the degree of normalization of central and peripheral BDNF levels. These findings suggest that rhythmic, weight-bearing exercise may be an effective intervention to counter SCI-induced allodynia.

Animals↗
PubMed2000

Polyunsaturated fatty acids are potent neuroprotectors.

Results reported in this work suggest a potential therapeutic value of polyunsaturated fatty acids for cerebral pathologies as previously proposed by others for cardiac diseases. We show that the polyunsaturated fatty acid linolenic acid prevents neuronal death in an animal model of transient global ischemia even when administered after the insult. Linolenic acid also protects animals treated with kainate against seizures and hippocampal lesions. The same effects have been observed in an in vitro model of seizure-like activity using glutamatergic neurons and they have been shown to be associated with blockade of glutamatergic transmission by low concentrations of distinct polyunsaturated fatty acids. Our data suggest that the opening of background K(+) channels, like TREK-1 and TRAAK, which are activated by arachidonic acid and other polyunsaturated fatty acids such as docosahexaenoic acid and linolenic acid, is a significant factor in this neuroprotective effect. These channels are abundant in the brain where they are located both pre- and post-synaptically, and are insensitive to saturated fatty acids, which offer no neuroprotection.

Animals↗
PubMed2002

Intracellular deposition, microtubule destabilization, and transport failure: an "early" pathogenic cascade leading to synaptic decline.

Protein deposition is a common event in age-related neurological diseases that are characterized by neuronal dysfunction and eventual cell death. Here, cultured hippocampal slices were infused with the lysosomal disrupter chloroquine to examine the link between abnormal protein processing/deposition and early synaptopathogenesis. Tau species of 55 to 69 kDa increased over several days of treatment with chloroquine, while the protein and message levels of synaptic markers were selectively reduced. Neurons of subfields CA1, CA3, and dentate gyrus accumulated protein deposits recognized by antibodies against paired helical filaments and ubiquitin, and this was accompanied by tubulin fragmentation and deacetylation. The deposition filled the basal pole of pyramidal neurons, encompassing the area of the axon hillock and initial dendritic branching but without causing overt neuronal atrophy. Neurons containing the polar aggregates exhibited severely impaired transport along basal dendrites. Transport capability was also lost along apical dendrites, the opposite direction of deposited material in the basal pole; thus, perpetuating the problem beyond physical blockage must be the associated loss of microtubule integrity. These data indicate that transport failure forms a link between tau deposition and synaptic decline, thus shedding light on how protein aggregation events disrupt synaptic and cognitive functions before the ensuing cellular destruction.

Aging↗
PubMed2004

Directed differentiation of embryonic stem cells into dorsal interneurons.

During neural development caudalization and dorsoventral patterning of the neural tube is directed by several inductive factors including retinoic acid, sonic hedgehog (Shh), bone morphogenetic proteins (BMPs), and Wnt signaling. The purpose of the current study was to investigate whether dorsal interneurons specific for the spinal cord can be generated from mouse embryonic stem (ES) cells using known inductive signals. Here we show that specific combination of developmental signaling molecules including all trans-retinoic acid, Shh, bone morphogenetic protein 2 (BMP2), and Wnt3A can direct differentiation of ES cells into dorsal interneurons possessing appropriate neuronal markers, synaptic proteins and functional neurotransmitter machineries. We introduce a concept that Wnt3A morphogenic action relies on crosstalk with both Shh and BMP2 signaling pathways.

Animals↗
PubMed1998

Monoclonal antibodies reveal expression of the CGRP receptor in Purkinje cells, interneurons and astrocytes of rat cerebellar cortex.

The molecular layer of adult rat cerebellum displays high levels of calcitonin gene-related peptide (CGRP) receptors, but the cellular location of the receptor remains unidentified. In an attempt to reveal the expression sites of these receptors, monoclonal antibodies raised against purified CGRP receptors from porcine cerebellar membranes were used in double-immunofluorescence experiments combined with confocal microscopy. PEP-19, a marker that is highly enriched in Purkinje cells (Pc), revealed that CGRP receptors are located in Pc cytoplasm and dendrites, where they label small puncta sometimes arranged in a row along the course of the dendrite itself. CGRP receptors were also located in inhibitory interneurons. Furthermore, as shown by double-labeling experiments with GFAP, CGRP receptor-IR labeled Golgi epithelial cells and their radial fibers (Bergmann fibers), as well as astrocytic processes encircling Pc somata. The simultaneous presence of CGRP receptors in Purkinje cells and in the glial cells that heavily enshroud Purkinje cells allows us to hypothesize that these receptors may be involved in neuron-glia interactions influencing neuronal activity.

Adrenomedullin↗
PubMedDate not supplied

Quinolone-resistant Neisseria gonorrhoeae in Hong Kong.

OBJECTIVE: To study the serologic characters and antibiotic susceptibilities of quinolone-resistant Neisseria gonorrhoeae in Hong Kong. STUDY DESIGN: Sixty-nine strains of Neisseria gonorrhoeae isolated from clinical failure cases after treatment with ofloxacin during the period January 1, 1992, to January 1, 1995, were studied. A panel of 14 monoclonal antibodies against protein I classified these strains into 21 serovars. The pattern of serovar distribution against varying minimum inhibitory concentrations of ofloxacin was compared with 143 strains isolated from a cohort of quinolone-susceptible, clinically responsive cases. Antibiotic susceptibilities tests were performed on quinolone-resistant strains to penicillin, tetracycline, ciprofloxacin, spectinomycin, and ceftriaxone. Epidemiologic information on location of contact was collected. RESULTS: Serologic characterization showed that Bop and Bpy were the dominant serovars among quinolone-resistant strains. Most IA and other IB serovars had declined in the selection process for quinolone resistance. Antibiotic susceptibility tests showed that 81.2%, 89.9%, and 78.3% of quinolone-resistant Neisseria gonorrhoeae strains were resistant to penicillin, tetracycline, and both, respectively, whereas 10 of 69 (14.5%) of such strains displayed high-level quinolone resistance (ofloxacin minimum inhibitory concentration > 8 micrograms/ml). The quinolone-resistant strains remained fully susceptible to spectinomycin and ceftriaxone. CONCLUSIONS: Quinolone-resistant strains have become firmly established in Hong Kong. Serovar determination has documented shifts in the gonococcal population during the selection process for quinolone resistance. Places that use quinolones in the treatment of sexually transmitted diseases should be alert to the emergence of high-level quinolone-resistant Neisseria gonorrhoeae.

Adolescent↗
PubMed1988

Nonbactericidal antibodies against Neisseria gonorrhoeae: evaluation of their blocking effect on bactericidal antibodies directed against outer membrane antigens.

Nonbactericidal monoclonal antibodies (MAbs) directed against gonococcal surface antigens were examined for their effect on complement-mediated bactericidal killing by other MAbs and normal human serum. One MAb, SM73, directed against the H.8 antigen activated complement only moderately well and had little influence on bactericidal antibodies. Two antibodies directed against an epitope on protein III had very different effects. Antibody SM51 activated complement poorly and had no effect on bactericidal killing, whereas antibody SM50, although itself nonbactericidal, activated complement and blocked the bactericidal effect of other antibodies. The extent of the blocking ability of MAb SM50 was studied using MAbs of different specificities as well as polyclonal antisera raised against gonococcal surface antigens. Antibody SM50 blocked IgG MAbs of all specificities, but several MAbs of the IgM class retained their bactericidal effect. Each of these IgM MAbs reacted with lipopolysaccharide, but with different epitopes.

Antibodies, Bacterial↗
PubMed2004

Environmental enrichment reverses learning impairment in the Morris water maze after focal cerebral ischemia in rats.

Cognitive impairment is common after ischemic stroke. In rodent stroke models using occlusion of the middle cerebral artery (MCA) this is reflected by impaired spatial memory associated with the size of the ischemic lesion. Housing in an enriched environment enhances brain plasticity and improves recovery of sensorimotor functions after experimental stroke in rats. In this study we report that postischemic housing in an enriched environment also attenuates the long-term spatial memory impairment after MCA occlusion and extinguishes the association between spatial memory and infarct volume. An enriched environment did not significantly alter the expression of selected neuronal plasticity-associated genes 1 month after MCA occlusion, indicating that most of the adaptive changes induced by an enriched environment have already occurred at this time point. We conclude that the attenuated memory impairment induced by environmental enrichment after MCA occlusion provides a useful model for further studies on the neurobiological mechanisms of recovery of cognitive functions after ischemic stroke.

Animals↗
PubMed2005

Internalized GABA-receptor subunits are transferred to an intracellular pool associated with the postsynaptic density.

Endocytosis represents an important mechanism regulating cell-surface expression of neurotransmitter receptors, including GABAA receptors, in neurons. Little is known, however, about trafficking of internalized receptors. Here, we used antibody tagging in living rat hippocampal neurons in culture to monitor GABAA receptor internalization. We show that cell-surface receptors have a homogeneous distribution reflecting their mobility in the membrane. Unexpectedly, internalized GABAA receptors were detected mainly in a subsynaptic pool associated with gephyrin at postsynaptic sites, whereas AMPA-type glutamate receptors were accumulated in the soma. This process was time-dependent and could be prevented by blocking clathrin-coated vesicle endocytosis. In control experiments, the existence of an intracellular pool of GABAA receptors associated with gephyrin was confirmed independently of internalization of surface receptors, and constitutive endocytosis, unrelated to antibody-tagging, could be demonstrated for both AMPA and GABAA receptors using a biotinylation assay. These results suggest that cycling of GABAA receptors between the cell surface and the subsynaptic pool provides a mechanism for the short-term regulation of GABAergic neurotransmission. Furthermore, the close association of gephyrin with internalized GABAA receptors suggests a role in intracellular receptor trafficking.

Animals↗
PubMed2006

Homeostatic plasticity during alcohol exposure promotes enlargement of dendritic spines.

Modifications of the size, shape and number of dendritic spines is thought to be an important component of activity-dependent changes of neuronal circuits, and may play an important role in the plasticity of drug addiction. The present study examined whether homeostatic increases in synaptic N-methyl-d-aspartate (NMDA) receptors in response to chronic ethanol exposure is associated with corresponding morphological changes in dendritic spines. Prolonged exposure of rat hippocampal cultures to either the NMDA receptor antagonist d(-)-2-amino-5-phosphono-pentanoic acid or to ethanol increased punctate staining of F-actin and the postsynaptic density protein-95 (PSD-95). The increase in dendritic F-actin occurred only with clusters that co-localized with PSD-95 clusters, indicating that these actin structures likely represent dendritic spines. The ethanol-induced increases in PSD-95 and F-actin clusters were activity-dependent and reversible. Finally, inhibition of protein palmitoylation prevented ethanol-induced increases in synaptic NMDA receptor clustering and F-actin without altering the basal clustering of either F-actin or PSD-95. These observations support a model in which chronic ethanol exposure induces homeostatic increases of NR2B-containing NMDA receptors and PSD-95 to the postsynaptic density. This in turn may provide a scaffolding platform for the subsequent recruitment of actin signaling cascades that alter actin cycling and promote spine enlargement.

Actins↗
PubMed1981

Presence of protein I, a phosphoprotein associated with synaptic vesicles, in cerebellar granule cells.

The cerebellar levels of Protein I, a synapse-specific neuronal phosphoprotein, have been investigated in the cerebellar mouse mutants stagger (sg), weaver (wv), nervous (nr), and Purkinje cell degeneration (pcd). The Protein I concentration was reduced by about 66% in sg and wv mutants, representing a 90% loss of Protein I per cerebellum. A heterozygote effect was observed in the wv mutant. These results indicate that a great majority of Protein I in the normal cerebellum may be present in the granule cells. In nr mutants the cerebellar Protein I concentration was reduced by only 12% in 62-day-old mice, suggesting that Purkinje cells contribute little to cerebellar Protein I. However, a greater reduction was observed in pcd mutants, which may reflect on the nature of the pcd mutation.

Animals↗
PubMed1981

Distribution of protein I, a synapse-specific phosphoprotein, and adenylate cyclase in the rat spinal cord.

The longitudinal and transverse distributions of the synapse-specific phosphoprotein Protein I and adenylate cyclase in the rat spinal cord were studied. Protein I was found to be enriched in all cervical and midlumbar (L3-L5) segments, and sparse in midthoracic and sacral segments. Adenylate cyclase activity was high in all cervical and lumbosacral segments, and low in mid-thoracic segments. Cross sectionally, both Protein I and adenylate cyclase were more enriched in the dorsal half than in the ventral half in the various segments studied. The similar topographical distributions of Protein I and adenylate cyclase in the spinal cord support the idea that adenylate cyclase may be intimately associated with Protein I in the nervous system, and could thereby regulate the state of in vivo phosphorylation of Protein I through formation of cyclic AMP.

Adenylyl Cyclases↗