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PubMed2005

Activity-dependent dendritic spine structural plasticity is regulated by small GTPase Rap1 and its target AF-6.

Activity-dependent remodeling of dendritic spines is essential for neural circuit development and synaptic plasticity, but the mechanisms that coordinate synaptic structural and functional plasticity are not well understood. Here we investigate the signaling pathways that enable excitatory synapses to undergo activity-dependent structural modifications. We report that activation of NMDA receptors in cultured cortical neurons induces spine morphogenesis and activation of the small GTPase Rap1. Rap1 bimodally regulates spine morphology: activated Rap1 recruits the PDZ domain-containing protein AF-6 to the plasma membrane and induces spine neck elongation, while inactive Rap1 dissociates AF-6 from the membrane and induces spine enlargement. Rap1 also regulates spine content of AMPA receptors: thin spines induced by Rap1 activation have reduced GluR1-containing AMPA receptor content, while large spines induced by Rap1 inactivation are rich in AMPA receptors. These results identify a signaling pathway that regulates activity-dependent synaptic structural plasticity and coordinates it with functional plasticity.

2-Amino-5-phosphonovalerate↗
PubMed2005

Non-targeted multi-component analytical surveillance of plastic food contact materials: Identification of substances not included in EU positive lists and their risk assessment.

A procedure used by the Norwegian Food Safety Authority for surveillance of contaminants from plastic food contact materials (polyolefin drinking bottles, water boilers, polyamide cooking utensils and plastic multi-layer materials) is described. It is based on gas chromatographic-mass spectrometric (GC/MS) analysis of food simulants exposed to plastic materials. Most migrants were substances not-intentionally added to the plastic (degradation products, impurities) or originated from non-plastic components, such as printing inks, adhesives, not-listed additives, solvents and coatings. Hence, the majority of the identified migrants were regulated by the general statements in the EU Framework Regulation, which neither specify limits nor requirements regarding risk assessment, rather than by specific migration controls. Risk assessment has been carried out for selected non-authorized substances. The analysis and the management of these substances and materials with respect to safety represents a challenge to the food authorities.

Aniline Compounds↗
PubMed1989

Organotypic slice cultures of dopaminergic neurons of substantia nigra.

Morphological methods were used to study the plasticity of target-deprived mammalian dopaminergic (DA) neurons. Slices of substantia nigra (SN) were taken from the midbrain of rats aged one to twelve days, and cultured for one to two weeks. Localization of tyrosine hydroxylase (TH) was used to examine the distribution and shapes of DA neurons. Histochemical staining for acetylcholinesterase (AChE) was carried out to estimate both survival and biosynthesis of SN neurons. We found that some DA neurons can survive in vitro without their usual target neurons. This was demonstrated by injecting rhodamine-conjugated microspheres (RD) into the caudate putamen, a SN target area, at 6 to 8 days prior to culturing. RD-labeled cells survived in SN cultures and some of them were doubly labeled with AChE. TH neurons had different shapes and their axon terminals formed close contacts with adjacent nondopaminergic neurons. These findings suggest that a subset of DA neurons may switch targets, but the majority of them require target interactions with the caudate putamen for survival in vitro.

Acetylcholinesterase↗
PubMed1991

Target-dependent structural changes in sensory neurons of Aplysia accompany long-term heterosynaptic inhibition.

FMRFamide evokes both short-term and long-term inhibition of synapses between mechanosensory and motor neurons in Aplysia. We report here, using dissociated cell culture and low-light epifluorescence video microscopy, that depression lasting 24 hr of sensorimotor synapses evoked by four brief applications of FMRFamide is accompanied by a significant loss of sensory cell varicosities and neurites. These structural changes in the sensory cells require the presence of the target motor cell L7. Because the loss of structures known to contain transmitter release sites correlates significantly with the changes in the amplitude of the excitatory postsynaptic potential in L7, our results suggest that the structural changes evoked by FMRFamide reflect a loss of synaptic contacts. Thus, long-term depression parallels long-term facilitation of the sensorimotor synapse produced by serotonin in that both forms of heterosynaptic plasticity involve target-dependent modulation of the number of presynaptic varicosities.

Animals↗
PubMed2006

Toward a multimodal neuroprotective treatment of stroke.

BACKGROUND AND PURPOSE: Stroke remains a common medical problem with importance attributable to the demographic changes in industrialized societies. SUMMARY OF REVIEW: After years of setbacks, acute stroke therapy has finally emerged, including thrombolysis with tissue plasminogen activator (t-PA). However, t-PA treatment is limited by a narrow time window and side effects, so that only 3% of all stroke patients receive thrombolysis. Unimodal targeting of key events in stroke pathophysiology was not effective in providing long-term benefits, leading to negative results in previous clinical neuroprotective stroke trials. A successful future stroke therapy should approach multiple pathophysiological mechanisms besides revascularization at once, including reduction of t-PA-related side effects, prevention of cell death, stimulation of neuroregeneration, and plasticity. CONCLUSIONS: Strategies targeting these processes include multiple combination therapies as well as treatment with multimodal drugs that interact with these mechanisms. Here, we review such combination approaches, and outline how this concept could be developed into future stroke treatment.

Animals↗
PubMed1988

Developmental interactions between sweat glands and the sympathetic neurons which innervate them: effects of delayed innervation on neurotransmitter plasticity and gland maturation.

The neurotransmitter properties of the sympathetic innervation of sweat glands in rat footpads have previously been shown to undergo a striking change during development. When axons first reach the developing glands, they contain catecholamine histofluorescence and immunoreactivity for catecholamine synthetic enzymes. As the glands and their innervation mature, catecholamines disappear and cholinergic and peptidergic properties appear. Final maturation of the sweat glands, assayed by secretory competence, is correlated temporally with the development of cholinergic function in the innervation. To determine if the neurotransmitter phenotype of sympathetic neurons developing in vivo is plastic, if sympathetic targets can play a role in determining neurotransmitter properties of the neurons which innervate them, and if gland maturation is dependent upon its innervation, the normal developmental interaction between sweat glands and their innervation was disrupted. This was accomplished by a single injection of 6-hydroxy-dopamine (6-OHDA) on Postnatal Day 2. Following this treatment, the arrival of noradrenergic sympathetic axons at the developing glands was delayed 7 to 10 days. Like the gland innervation of normal rats, the axons which innervated the sweat glands of 6-OHDA-treated animals acquired cholinergic function and their expression of endogenous catecholamines declined. The change in neurotransmitter properties, however, occurred later in development than in untreated animals and was not always complete. Even in adult animals, some fibers continued to express endogenous catecholamines and many nerve terminals contained a small proportion of small granular vesicles after permanganate fixation. The gland innervation in the 6-OHDA-treated animals also differed from that of normal rats in that immunoreactivity for VIP was not expressed in the majority of glands. It seems likely that following treatment with 6-OHDA sweat glands were innervated both by neurons that would normally have done so and by neurons that would normally have innervated other, noradrenergic targets in the footpads, such as blood vessels. Contact with sweat glands, therefore, appears to suppress noradrenergic function and induce cholinergic function not only in the neurons which normally innervate the glands but also in neurons which ordinarily innervate other targets. Effects of delayed innervation were also observed on target development. The appearance of sensitivity to cholinergic agonists by the sweat glands was coupled with the onset of cholinergic transmission.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed2026

Epigenetic Repression of TP53 Transcription Underlies Cancer Cell Persistence for Carboplatin Resistance in Non-Small Cell Lung Cancer.

While chemoresistance in non-small cell lung cancer (NSCLC) cells has historically been attributed to permanent genetic mutations, emerging evidence highlights the role of nongenetic transcriptional plasticity and 'drug-tolerant persister' cells. To systematically map these epigenetic vulnerabilities, we utilized a genome-wide CRISPR interference library to screen wild-type TP53 NSCLC (A549) cells under carboplatin selection. Using the DrugZ algorithm and subsequent pathway enrichment analyses, this screen revealed that transcriptional suppression of interstrand crosslink DNA repair networks, including the Fanconi anemia pathway, markedly sensitized cells to carboplatin. Unexpectedly, transcriptional silencing of TP53 and its downstream target CDKN1A emerged as the strongest drivers of resistance, enabling cells to bypass therapy-induced senescence and maintain their proliferative potential later. To validate these findings in a clinically relevant context, we established a chronic carboplatin-resistant cell model (A549CarboR cells). A549CarboR exhibited a reduction in TP53 transcripts, along with decreased H3K27 acetylation and increased DNA hypermethylation on its promoter. Epigenetic remodeling using the DNA methyltransferase inhibitor (DNMTi) was associated with unblocking TP53 transcription, restored p53 signaling, and resensitization of resistant cells to carboplatin. Conversely, histone deacetylase inhibitors induced CDKN1A transcription to bypass TP53, indicating distinct epigenetic circuits. Collectively, the results demonstrate for the first time that TP53 expression is dynamically regulated at the transcriptional level through promoter methylation related to the drug tolerance. These insights emphasize that epigenetic silencing, rather than exclusive genetic loss-of-function, contribute to platinum resistance and underscore the therapeutic potential of pairing platinum regimens with DNMTi to target the transcriptomic plasticity of persistent cancer cell populations.

CRISPR interference screening↗
PubMed2000

Biochemical and functional aspects of gonadotrophin-releasing hormone and gonadotrophins.

Reproductive function in mammals is governed by the hypothalamic-pituitary-gonadal axis, which conforms a functional unit. Sexual maturation and the subsequent development of reproductive competence depend on the precise and coordinated function of this axis. The components of the reproductive axis communicate each other through endocrine signals. The hypothalamus synthesizes gonadotrophin-releasing hormone or GnRH, which in turn stimulates synthesis and secretion of the pituitary gonadotrophins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The ovarian follicles and the interstitial and Sertoli cells of the testis are the targets for these pituitary signals. Under gonadotrophic stimulation, the gonads produce and secrete several steroid and non-steroid (polypeptide) factors, which in turn regulate in different ways the function of the hypothalamic-pituitary axis. An episodic and pulsatile mode of secretion of hormonal signals characterize (as in other endocrine systems) the function of the reproductive axis, particularly that of the hypothalamic-pituitary unit. The target cell response, and consequently the harmonic function of the corresponding gland, will depend on the adequate dynamics of this pulsatile secretion. The function of each component of the reproductive axis is strongly influenced by locally-produced signals acting either in a paracrine or autocrine manner; these particular signals represent fine-tuning regulation systems that eventually amplify or restrain the magnitude of response to a particular endocrine signal, providing additional mechanisms for tissue homeostasis and a better functional plasticity of the target gland. The design and rational use of novel therapeutic strategies for an optimal exogenously-controlled reproductive function largely depend on the detailed knowledge of the hypothalamic-pituitary-gonadal axis function and the structure and mechanism of action of those factors and signals involved in its regulation.

Journal Article↗
PubMed2002

The Nogo receptor, its ligands and axonal regeneration in the spinal cord; a review.

At least three proteins present in CNS myelin, Nogo, MAG and OMgp are capable of causing growth cone collapse and inhibiting neurite outgrowth in vitro. Surprisingly, Nogo and OMgp are also strongly expressed by many neurons (including neocortical projection cells). Nogo expression is increased by some cells at the borders of CNS lesion sites and by cells in injured peripheral nerves, but Nogo and CNS myelin are largely absent from spinal cord injury sites, which are none the less strongly inhibitory to axonal regeneration. Nogo is found on growing axons during development, suggesting possible functions for neuronal Nogo in axon guidance. Although Nogo, MAG and OMgp lack sequence homologies, they all bind to the Nogo receptor (NgR), a GPI-linked cell surface molecule which, in turn, binds p75 to activate RhoA. NgR is strongly expressed by cerebral cortical neurons but many other neurons express NgR weakly or not at all. Some neurons, such as DRG cells, respond to Nogo and CNS myelin in vitro although they express little or no NgR in vivo which, with other data, indicates that other receptors are available for NgR ligands. NgR expression is unaffected by injury to the nervous system, and there is no clear correlation between NgR expression by neurons and lack of regenerative ability. In the injured spinal cord, interactions between NgR and its ligands are most likely to be important for limiting regeneration of corticospinal and some other descending tracts; other receptors may be more important for ascending tracts. Antibodies to Nogo, mainly the poorly-characterised IN-1 or its derivatives, have been shown to enhance recovery from partial transections of the spinal cord. They induce considerable plasticity from the axons of corticospinal neurons, including sprouting across the midline and, to a limited extent, regeneration around the lesion. Regeneration of corticospinal axons induced by Nogo antibodies has not yet been demonstrated after complete transections or contusion injuries of the spinal cord. It is not clear whether antibodies against Nogo act on oligodendrocytes/myelin or by binding to neuronal Nogo, or whether they can stimulate regeneration of ascending axons in the spinal cord, most of which express little or no NgR. Despite these uncertainties, however, NgR and its ligands offer important new targets for enhancing plasticity and regeneration in the nervous system.

Animals↗
PubMed1990

Ultrastructural changes during lysis of L929 target cells by class II-restricted influenza virus-specific murine cytotoxic T-lymphocyte clones.

Lysis of virus-infected L929 target cells transfected with the H-2 class II IAk gene by class II-restricted influenza virus-specific murine cytotoxic T lymphocyte (CTL) clones was studied by electron microscopy and compared with lysis of L929 cells by class I-restricted CTL clones. T lymphocytes predominantly approached the basal surface of target cells grown on a plastic dish and also approached uninfected L929 target cells, although virus maturation exhibited no polarity with respect to the cell surface site. After incubation for 30 min, the target cell nuclei began to change: chromatin became irregularly redistributed and aggregated, and the nuclei appeared swollen. Later, electron-dense and -light areas of nuclei became segregated, and the cytoplasm became disorganized with many vacuoles. The ultrastructural changes of target cells during lysis by class I- and class II-restricted CTL clones appeared to be similar. These findings and other cytotoxicity data of class I and class II CTLs are discussed.

Animals↗
PubMed2003

Plasticity following injury to the adult central nervous system: is recapitulation of a developmental state worth promoting?

The adult central nervous system (CNS) appears to initiate a transient increase in plasticity following injury, including increases in growth-related proteins and generation of new cells. Recent evidence is reviewed that the injured adult CNS exhibits events and patterns of gene expression that are also observed during development and during regeneration following damage to the mature peripheral nervous system (PNS). The growth of neurons during development or regeneration is correlated, in part, with a coordinated expression of growth-related proteins, such as growth-associated-protein-43 (GAP-43), microtubule-associated-protein-1B (MAP1B), and polysialylated-neural-cell-adhesion-molecule (PSA-NCAM). For each of these proteins, evidence is discussed regarding its specific role in neuronal development, signals that modify its expression, and reappearance following injury. The rate of adult hippocampal neurogenesis is also affected by numerous endogenous and exogenous factors including injury. The continuing study of developmental neurobiology will likely provide further gene and protein targets for increasing plasticity and regeneration in the mature adult CNS.

Adult↗
PubMed1999

Short-term plasticity in primary somatosensory cortex of the rat after hindlimb suspension.

Since the last 25 years, the cortex is considered as a dynamic entity, susceptible of changes. Various types of modifications in stimuli may lead to the plasticity of the target neurons. These include immobilisation, denervation, amputation, deafferentation... In the somatosensory system, the most important changes are a substantial reorganisation of the cortical somatotopic representation, and an enlargement of the receptive fields (RF) of cortical neurons. Hindlimb suspension (HS) is characterized by the absence of weight-bearing and a reduced motor activity. In these conditions, the cutaneous receptors located on the foot sole are deactivated. Our hypothesis is that this condition of HS can produce a reorganisation of the somatosensory cortex (SmI) and a modification in the size of the cutaneous RF.

Animals↗
PubMed1996

Neuropeptide localization in varicosities of Aplysia sensory neurons is regulated by target and neuromodulators evoking long-term synaptic plasticity.

The synapses between the sensory neuron (SN) and motor neuron of Aplysia undergo long-term functional and structural modulation with appropriate behavioral training or with applications of specific neuromodulators. Expression of molecules within the presynaptic terminals may be regulated in parallel with the changes evoked by the neuromodulators. We examined with immunocytochemical methods whether the level of sensorin, the SN-specific neuropeptide, is modulated in SN varicosities by the location of interaction with the target motor cell L7 and by applications of either 5-HT that evoke long-term facilitation or FMRFamide that evoke long-term depression of Aplysia sensorimotor connections in vitro. A significantly higher proportion of SN varicosities are sensorin positive when they are in contact with the proximal axons of L7 compared to varicosities of the same SNs in contact with distal L7 neurites. Both 5-HT and FMRFamide evoked changes in the efficacy and structure of sensorimotor connections that are accompanied by changes in the frequency of sensorin-positive varicosities contacting the axons of L7. More preexisting SN varicosities are stained after 5-HT, and fewer preexisting SN varicosities are stained after FMRFamide. These results suggest that the postsynaptic target and the neuromodulators not only regulate overall structure but also regulate the level of SN neuropeptide at synaptic sites.

Animals↗
PubMed2006

Fluoxetine reverses stress-induced fimbria-prefrontal long-term potentiation facilitation.

Stress has been reported to disrupt the induction of synaptic plasticity in different fimbria target structures. The aim of the present study was to investigate whether chronic mild stress may also affect synaptic plasticity in the medial prefrontal cortex, a fimbria target structure. Fimbria tetanus (100 Hz) did not produce any changes in medial prefrontal cortex synaptic efficacy in non-stressed rats. Rats exposed to chronic mild stress, however, developed significant long-term potentiation. Treatment with fluoxetine (10 mg/kg, intraperitoneal) suppressed long-term potentiation induction in the chronic mild stress group. These data demonstrate that stress not only inhibits long-term potentiation development, as often demonstrated, but can also facilitate long-term potentiation development in certain brain circuits.

Animals↗
PubMed2000

Hippocampo-prefrontal cortex pathway: anatomical and electrophysiological characteristics.

The hippocampus, the prefrontal cortex, and interconnected neural circuits are implicated in several aspects of cognitive and memory processes. The present review is dedicated to the description of the anatomo-functional characteristics of the hippocampo-prefrontal pathway and related neuronal circuits in the rat. This pathway, which originates from the hippocampal CA1/subiculum fields, innervates the prelimbic/medial orbital areas of the prefrontal cortex (PL/MO). Its synaptic influence on cortical pyramidal neurons consists in an early monosynaptic excitation followed by an inhibition and, in some cases, a late excitation. These later effects are likely due to the subsequent activation of the local cortical network. PL/MO areas and the CA1/subiculum both send projections to the nucleus accumbens, a region of the ventral striatum which is particularly implicated in goal-directed behavior. Therefore, emphasis is placed on respective projections from PL/MO areas and from the CA1/subiculum on the "core" and the "shell" regions of the nucleus accumbens, as well as on their interconnected circuits. Signals which are directed to the prefrontal cortex through these circuits might modulate hippocampo-prefrontal inputs. Finally, the direct and/or indirect relationships of the hippocampus, prefrontal cortex, and nucleus accumbens with the ventral tegmental area/substantia nigra pars compacta complex (VTA/SNC) (where dopamine neurons are located) will also be described, because these neurons are known to modulate synaptic transmission and plasticity in their target structures and to play a fundamental role in motivational processes.

Animals↗
PubMed2002

Gamma Knife surgery, a neuromodulation therapy in epilepsy surgery!

INTRODUCTION: The more classical approach for Epilepsy surgery is the removal of the epileptogenic zone (ZE). We present a critical review of information in favor of a possible non-destructive effect of radiosurgery in epilepsy surgery. MATERIAL: Clinical material of patients with epilepsies related to a lesion in highly functional areas subjected to radiosurgery with relief of the seizures and no functional worsening is available. We applied direct treatment of the EZ with good efficacy in the absence of destructive aspects on the MR and no functional deterioration (e.g. hypothalamic hamartomas). Experimental studies have shown biochemical differential effect of radiosurgery on the striatum, glial cell elimination, stem cell migration toward the target area, sprouting,... Plasticity phenomenon are induced by radiosurgery when using non necrotizing dosemetry. DISCUSSION: There is clinical and experimental evidence of Gamma Knife capability to induce modulation in the neural system. Detailed mechanism of this modulation and dosemetric parameters enabling to induce such plasticity with no necrosis are still unknown. Subpial transection turning out actually to be quite disappointing, there is a specific rationale to test radiosurgery capability to treat EZ cortex while preserving the underlying function of this cortex when the functional risk for cortectomy is too high.

Brain Diseases↗
PubMed1993

Cloning and characterization of a cDNA encoding the cytosolic copper/zinc-superoxide dismutase from sweet potato tuberous root.

A full-length cDNA clone encoding a putative copper/zinc-superoxide dismutase (SOD) of sweet potato, Ipomoea batatas (L.) Lam. cv Tainong 57, was isolated from a cDNA library constructed in lambda gt10 from tuber root mRNA. Nucleotide sequence analysis of this cDNA clone revealed that it comprises a complete open reading frame coding for 152 amino acid residues. The deduced amino acid sequence showed higher homology (78-86%) with the sequence of the cytosolic SOD than that of the chloroplast SOD from other plant species. The residues required for coordinating copper and zinc are conserved as they are among all reported Cu/Zn-SOD sequences. In addition, it lacks recognizable plastic or mitochondrial targeting sequences. These data suggest that the isolated sweet potato clone encodes a cytosolic Cu/Zn-SOD.

Amino Acid Sequence↗
PubMed1987

Human T4+ T-lymphocyte clones specific for the B fragment of tetanus toxin.

Two T4+ cloned T-lymphocyte lines specific for a papain digest product of tetanus toxin are functionally characterized. The two clones were obtained from peripheral blood mononuclear cells activated in vitro by tetanus toxoid, expanded with IL-2, and cloned in soft agar. Both clones could be induced to undergo blastogenesis with tetanus toxoid, tetanus toxin, and the B fragment but not the C fragment of tetanus toxin. In addition, both clones caused cytolysis of plastic adherent cell targets cocultured for 18 hr with either tetanus or the B fragment. Antigen specific proliferation and cytolytic activity were MHC-class I restricted.

Cell Line↗