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PubMed2004

Host Cell Phenotypic Variability Induced by Trypanosomatid-Parasite-Released Immunomodulatory Factors: Physiopathological Implications.

The parasitic protozoa Trypanosoma cruzi and Leishmania sp release a variety of molecules into their mammalian hosts (ESA: excretory-secretory products). The effects of these ESA on the host cell function may participate in the establishment of a successful infection, in which the parasite persists for a sufficient period of time to complete its life cycle. A number of regulatory components or processes originating from the parasite that control or regulate the metabolism and the growth of host cell have been identified. The purpose of the present review is to analyze some of the current data related to the parasite ESA that interfere with the host cell physiology. Special attention is given to members of conserved protein families demonstrating remarkable diversity and plasticity of function (ie, glutathione S-transferases and related molecules; members of the trans-sialidase and mucin family; and members of the ribosomal protein family). The identification of parasite target molecules and the elucidation of their mode of action toward the host cell represents a step forward in efforts aimed at an immunotherapeutic or pharmacological control of parasitic infection.

Journal Article↗
PubMed2005

Neuromuscular contacts induce nitric oxide signals in skeletal myotubes in vitro.

It has previously been shown that skeletal myotubes express nitric oxide synthase (NOS) and produce and release NO signals. NOS is also part of agrin-induced acetylcholine receptor aggregations on myotubes. As nerve-muscle interactions underlie reciprocal signaling mechanisms, we hypothesized that NO signals in target myotubes may be induced by neuromuscular contacts in development. Chimeric neuron-myotube co-cultures were prepared using p75-selected spinal cord neurons from embryonic chicken. Confocal imaging revealed robust 1,2-diaminoanthraquinone red fluorescence indicative of de novo formation of NO only in those myotubes which were contacted by neurites, also verified by pre- and postsynaptic marker costaining (anti-synaptotagmin and alpha-bungarotoxin). Neither soluble agrin nor sensory dorsal root ganglionic neurons showed comparable effects in this model. We concluded that in target skeletal muscle cells the NOS/NO system is controlled by motoneuron contacts by as yet incompletely understood signaling mechanisms. Endogenous NO signaling in myotubes may be essential during synapse formation and plasticity of the neuromuscular system.

Animals↗
PubMed1991

Natural killer activity of human liver-derived lymphocytes in various liver diseases.

Liver-derived lymphocytes were isolated from 40 human livers with end-stage liver disease that were removed at the time of orthotopic liver transplantation. In addition, 10 resection specimens or whole livers removed from patients with liver cancer and seven normal livers (unused donor organs) were studied as controls. Liver-derived lymphocytes were isolated from enzymatically digested tissue by gradient centrifugation and adherence to plastic. Their phenotypical characteristics were studied by two-color flow cytometry, and effector cell function was determined in 4-hr 51Cr-release assays against a natural killer-sensitive target, K562 (natural killer activity), natural killer-resistant Daudi line (lymphokine-activated killer activity) and by P815 line with or without phytohemagglutinin to assess lectin-dependent cellular cytotoxicity. Liver-derived lymphocytes isolated from normal liver contained equal proportions of T and natural killer lymphocytes (mean natural killer/T ratio = 0.7). CD3-CD56+CD16- natural killer cells were the main natural killer subset present in liver-derived lymphocytes, in contrast to the predominant natural killer phenotype in the circulation (CD56+CD16+). Control liver-derived lymphocytes had levels of cytotoxicity significantly greater than those of the normal peripheral-blood lymphocytes against all three targets. In contrast, liver-derived lymphocytes isolated from organs with advanced liver disease differed markedly in the natural killer/T cell ratio and levels of liver-derived lymphocyte cytotoxicity. Liver-derived lymphocytes obtained from hepatocellular carcinoma or rejecting allografts treated by immunosuppressive therapy had virtually no cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2003

Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications.

gamma-Aminobutyric acid(A) (GABA(A)) receptors mediate most of the fast inhibitory neurotransmission in the CNS. They represent a major site of action for clinically relevant drugs, such as benzodiazepines and ethanol, and endogenous modulators, including neuroactive steroids. Alterations in GABA(A) receptor expression and function are thought to contribute to prevalent neurological and psychiatric diseases. Molecular cloning and immunochemical characterization of GABA(A) receptor subunits revealed a multiplicity of receptor subtypes with specific functional and pharmacological properties. A major tenet of these studies is that GABA(A) receptor heterogeneity represents a key factor for fine-tuning of inhibitory transmission under physiological and pathophysiological conditions. The aim of this review is to highlight recent findings on the regulation of GABA(A) receptor expression and function, focusing on the mechanisms of sorting, targeting, and synaptic clustering of GABA(A) receptor subtypes and their associated proteins, on trafficking of cell-surface receptors as a means of regulating synaptic (and extrasynaptic) transmission on a short-time basis, on the role of endogenous neurosteroids for GABA(A) receptor plasticity, and on alterations of GABA(A) receptor expression and localization in major neurological disorders. Altogether, the findings presented in this review underscore the necessity of considering GABA(A) receptor-mediated neurotransmission as a dynamic and highly flexible process controlled by multiple mechanisms operating at the molecular, cellular, and systemic level. Furthermore, the selected topics highlight the relevance of concepts derived from experimental studies for understanding GABA(A) receptor alterations in disease states and for designing improved therapeutic strategies based on subtype-selective drugs.

Animals↗
PubMed1990

Role of natural killer cells and macrophages in the nonspecific resistance to tumors in mice stimulated with SMANCS, a polymer-conjugated derivative of neocarzinostatin.

Copoly(styrene-maleic acid)-conjugated neocarzinostatin (SMANCS), a lipophilic derivative of the proteinaceous antitumor antibiotic neocarzinostatin, has been reported to stimulate a nonspecific resistance to tumors (NSRT) in solid tumor-bearing mice, in addition to its chemotherapeutic antitumor effect through the arrest of DNA synthesis by direct DNA strand scission. In the present study, splenic or peritoneal effector cells were used to investigate the ability of SMANCS to augment natural killer (NK) cell activity and to generate cytostatic macrophages (A-M phi). Splenic NK cell activity augmented by SMANCS was characterized by cytotoxicity to various target cells, nylon wool nonadherence, and sensitivity to treatment with anti-asialo-GM1 antiserum or monoclonal anti-Thy-1.2 antibody followed by complement. The A-M phi generated by SMANCS stimulation were characterized by their adherence to a plastic surface coated with fetal calf serum and their ability to phagocytize carbonyl-iron. The maximum level of NK cell activity in the spleens of mice was detected 3 days after i.v. injection of SMANCS, and the highest activity of the peritoneal A-M phi was demonstrated in mice 4 days after SMANCS treatment. On the other hand, the NSRT of mice stimulated with SMANCS was not detectable in mice treated with carrageenan or trypan blue, whereas SMANCS-stimulated NSRT was observed in mice treated with anti-asialo-GM1 antiserum. The NSRT that was stimulated with SMANCS was also demonstrated in mice homozygous for the beige mutation and their non-beige littermates, when NK cell-resistant EL-4 thymoma was used as a tumor target. These results suggest that the expression of NSRT of mice stimulated with SMANCS may require the function of A-M phi, although NK cell activity was also augmented in spleens of mice by administration of SMANCS.

Animals↗
PubMed2000

Brain plasticity and cellular mechanisms of epileptogenesis in human and experimental cortical dysplasia.

PURPOSE: The cellular mechanisms that may contribute to epilepsy in resected human cortical dysplasia (CD) were compared with the in utero radiated rat CD model. In human and rat focal hippocampal epilepsy, postsynaptic N-methyl-D-aspartate receptors are up-regulated and presynaptic axon collaterals hyperinnervate them. We hypothesized that in both human and rat CD: (a) the N-methyl-D-aspartate receptor subunits NR1 and NR2A/B would be increased and coassembled, and (b) aberrant axons would be in regions of CD. METHODS: Tests for presynaptic and postsynaptic changes in human and rat CD included the following: (a) cytology, (b) immunocytochemistry, (c) coimmunoprecipitation, (d) double-labeled immunofluorescence, and (e) Timm histochemistry of hippocampal mossy fibers. Within-patient comparisons were made between epileptic tissue, identified by subdural electro-encephalographic seizure onsets, and nonepileptic tissue remote from the focus but within the therapeutic resection. Rats were radiated at embryonic day 17, and offspring were studied postnatally. Statistical comparisons were made against normal rats matched for age and tissue processing. RESULTS: In focal CD patients, NR2A/B subunits and their coassemblies with NR1 were increased significantly more than for the remote nonepileptic cortex. Confocal microscopy showed that NR1-NR2A/B colabeled single dysplastic neurons in both human and rat. In CD rats, mossy fibers innervated the anomalously oriented hippocampal neurons. CONCLUSIONS: Human epileptic CD exhibits a spectrum of abnormal cell orientations and laminations that must require plastic axodendritic changes during development. These altered circuits and receptors could account for the seizures and cognitive deficits found in patients with CD. The radiated rat CD model with cortical dyslaminations and NR2A/B subunit increases would allow the development and testing of drugs targeted at only the NR2A/B subunit or at decoupling the NR1-NR2 coassembly, which could provide a specific antiepileptic drug for dysplastic circuits without inducing general depression of all brain neurons.

Abnormalities, Radiation-Induced↗
PubMed2004

Plasticity of the adult avian song control system.

There is extensive plasticity of the song behavior of birds and the neuroendocrine circuit that regulates this behavior in adulthood. One of the most pronounced examples of plasticity, found in every species of seasonally breeding bird examined, is the occurrence of large seasonal changes in the size of song control nuclei and in their cellular attributes. This seasonal plasticity of the song circuits is primarily regulated by changes in the secretion and metabolism of gonadal testosterone (T). Both androgenic and estrogenic sex steroids contribute to seasonal growth of the song system. These steroids act directly on the forebrain song nucleus HVC, which then stimulates growth of its efferent target nuclei transsynaptically. Seasonal growth and regression of the song circuits occur rapidly and sequentially following changes in circulating T and its metabolites. As the neural song circuits change across seasons, there are changes in different aspects of song behavior, including the structural stereotypy of songs, their duration, and the rate of production. The burden of evidence supports a model in which changes in song behavior are a consequence rather than a cause of the changes in the song circuits of the brain. Seasonal plasticity of the song system may have evolved as an adaptation to reduce the energetic demands imposed by these regions of the brain outside the breeding season, when the use of song for mate attraction and territorial defense is reduced or absent. The synaptic plasticity that accompanies seasonal changes in the song system may have acted as a preadaptation that enabled the evolution of adult song learning in some species of birds.

Adaptation, Physiological↗
PubMed2003

Integrating polymerase chain reaction, valving, and electrophoresis in a plastic device for bacterial detection.

An integrated plastic microfluidic device was designed and fabricated for bacterial detection and identification. The device, made from poly(cyclic olefin) with integrated graphite ink electrodes and photopatterned gel domains, accomplishes DNA amplification, microfluidic valving, sample injection, on-column labeling, and separation. Polymerase chain reaction (PCR) is conducted in a channel reactor containing a volume as small as 29 nL; thermal cycling utilizes screen-printed graphite ink resistors. In situ gel polymerization was employed to form local microfluidic valves that minimize convective flow of the PCR mixture into other regions. After PCR, amplicons (products) are electrokinetically injected through the gel valve, followed by on-chip electrophoretic separation. An intercalating dye is admixed to label the amplicons; they are detected using laser-induced fluorescence. Two model bacteria, Escherichia coli O157 and Salmonella typhimurium, were chosen to demonstrate bacterial detection and identification based on amplification of several of their unique DNA sequences. The limit of detection is about six copies of target DNA.

Bacteria↗
PubMed1986

Non-cholinergic afferents determine the distribution of the cholinergic septohippocampal projection: a study of the AChE staining pattern in the rat fascia dentata and hippocampus after lesions, X-irradiation, and intracerebral grafting.

The acetylcholinesterase (AChE) activity of the rat hippocampus and fascia dentata depends on an intact septohippocampal connection, and histochemical staining for AChE is commonly used to monitor the distribution of the cholinergic septohippocampal projection. It is also characteristic that the laminae of low or moderate to dense AChE staining in the hippocampus and fascia dentata coincide with the terminal fields of the major non-cholinergic, afferent pathways. While studying lesion-induced collateral sprouting and aberrant axonal growth of these pathways we observed that the AChE staining pattern changed in accordance with the reorganized distribution of the non-cholinergic pathways, and this occurred even without direct interfering with the septohippocampal projection itself. Widening and narrowing of the medial perforant path and mossy fiber terminal zones thus resulted in corresponding changes in the bands of AChE staining normally associated with these zones. Expansion of the commissural-associational hippocampodentate projections and the lateral perforant path was in a similar way paralleled by a widening of the AChE-poor zones which normally overlap with the termination of these projections. Observations of the same kind were made in intracerebral transplants of fascia dentata innervated by various host afferents, and in rats subjected to neonatal X-irradiation, where the mossy fiber projection is reduced and aberrant perforant pathways project into CA3 due to a reduced formation of granule cells. The observed sets of changes with linkage between the different non-cholinergic projections and the activity of AChE in their respective terminal fields were accordingly reproduced under several different experimental conditions. It could not be explained alone by interaction between the septal afferents and their target cells. We therefore conclude that the density and laminar distribution of the AChE activities within the hippocampus and fascia dentata are determined at least in part by the major afferent, non-cholinergic nerve connections. We suggest that the effect occurs through direct axonal interaction or through changes in the receptiveness of the common dentate and hippocampal target cells.

Acetylcholinesterase↗
PubMed1986

Hippocampal sympathetic ingrowth in rats and guinea pigs: quantitative morphometry and topographical differences.

Sympathetic ingrowth is an unusual neural rearrangement in response to damage of the septohippocampal pathway in which peripheral noradrenergic nerves grow into the hippocampal formation. Hippocampal ingrowth has been extensively studied in rats and has been suggested to be regulated by the mossy fibers of the dentate granule cells, hippocampal interneurons, or glial cells. Sympathetic ingrowth was found to occur in both rats and guinea pigs; however, a discrepancy between the species was observed in the topographical distribution of sympathetic ingrowth. Ingrowth fibers were found in the dentate hilus and area CA3 of guinea pigs and rats. However, in the guinea pig fibers extended into area CA1. Quantitative estimates of fiber number confirmed these observations and identified significant differences between the species in the intrahippocampal lamellar distribution of ingrowth fibers. The topographical differences in sympathetic ingrowth could not be explained by differences in the distribution of the mossy fibers (Timms stain), cholinergic septal afferents (anterograde HRP), or in hippocampal interneurons (GAD-immunoreactive neurons). These species differences are challenging to current theories concerning the regulation of sympathetic ingrowth and may provide a useful model for testing further hypotheses about axonal guidance and target selection.

Animals↗
PubMed1989

Regulation of granule cell number by a predetermined number of Purkinje cells in development.

Development dysgenesis of Purkinje cells or granule cells was analyzed for the reciprocal effect of reduced number of each cell type on the other. A single pre- or postnatal injection of methylazoxymethanol acetate (MAM) in the rat reduces either the number of Purkinje cells or the number of granule cells when administered at the time of their respective genesis. The total number of these two types of neurons was obtained from cell density values of each layer and the total volume of the granular layer and the area of the Purkinje cell layer. The results show that Purkinje cells (targets) strictly determine the maximum number of granule cells (afferent neurons) following deficits in the number of Purkinje cells produced by prenatal MAM administration. Deficits in Purkinje cells were accompanied by a proportionally smaller number of granule cells so that the ratio remained constant. On the other hand, the reduction in the number of granule cells of the postnatal MAM model did not affect the number of Purkinje cells. These results indicate that the maximum number of these afferent neurons is constrained unidirectionally through a property defined by the number of their target neurons which develop earlier. Furthermore the number of afferent cells had no effect on the number of target cells.

Animals↗
PubMed1989

Long-distance fiber outgrowth from the heterotopically transplanted olfactory bulb in the rat.

An embryonic olfactory bulb was heterotopically inserted and allowed to mature in young adult rat brains. The projection of the transplanted olfactory bulb to the host brain was examined by injections of peroxidase-labeled wheatgerm agglutinin into the host olfactory bulb (and anterior olfactory nucleus). Neurite elongation to the host olfactory area occurred most frequently from the transplant which had been inserted into the anterior horn of the lateral ventricle and fused medially with the lateral septum in host brains with no detectable damage of host olfactory connections. Transplants in the septum, olfactory tubercle, nucleus of the horizontal limb of the diagonal band, or anterior piriform cortex also showed the projection to the host olfactory area. These results indicate that the transplanted olfactory bulb projection neurons have potent abilities to detect the target and project to it even if there is a considerable distance (2-5 mm).

Animals↗
PubMed2002

Context-specific spatial representations by lateral septal cells.

To test whether the location coding of lateral septal cells is dependent on cue constellations, we examined single units in two different recording arenas on alternating days. Repeated recordings of lateral septal neurons in the same arena revealed that matching locations are encoded on separate days by about one third of the cells. The cells typically showed location-selective firing in only one of the two recording arenas and initially showed unrelated patterns when tested in a different recording arena. When tested for a second time in each recording arena, the initially dissimilar patterns were modified towards increased similarity between arenas. Simultaneously recorded hippocampal principal cells showed distinct place fields for each recording arena throughout the recording sequence. These results indicate that the initial reorganization of the lateral septal location coding may occur as a direct consequence of the hippocampal reorganization. Further septal reorganization is then partially independent of established place fields in the CA1 and CA3 area.Location-selective cells in cortical areas that receive projections from hippocampus proper (i.e. the subiculum and the entorhinal cortex) have not been shown to encode differences between recording arenas. Although some characteristics of this generalized coding scheme have also been found for location-selective lateral septal cells, the encoding of context information was generally preserved in the subcortical target cells of projections from the CA1 and CA3 area.

Animals↗
PubMed1999

Phenotype changes of inferior olive neurons following collateral reinnervation.

Inferior olive neurons are able to enlarge or retract their axonic terminal fields in response to changes in the extension of their target domain. Following Purkinje cell loss, the retraction of target-deprived climbing fibres is accompanied by a size reduction in the inferior olive neuron cell bodies. Here, we asked whether perikaryal modifications also occur when inferior olivary neurons enlarge their terminal fields to innervate supernumerary targets. To achieve this aim, we carried out a morphometric analysis on the somatic compartment of inferior olive neurons in two experimental conditions known to induce an expansion of their terminal field, i.e. a subtotal 3-acetylpyridine inferior olive lesion in the adult and a unilateral transection of the inferior cerebellar peduncle in newborn rats. In both experimental conditions, the inferior olive neurons that survived the lesion showed a remarkable increase in cell body and nuclear size, although the latter change was less pronounced in the 3-acetylpyridine-treated animals. These results show that both developing and mature inferior olive neurons are capable of adjusting their perikaryal phenotype to match the modifications of their target size.

Animals↗
PubMed2004

Accessories to addiction: G protein regulators play a key role in cocaine seeking and neuroplasticity.

The prefrontal cortex mediates many aspects of addiction. In this issue of Neuron, Bowers et al. demonstrate that an activator of G protein signaling (AGS3) is persistently upregulated in the prefrontal cortex after cessation of chronic cocaine treatment. Furthermore, they find that AGS3 is responsible for altered behavior, such as enhanced drug seeking, and altered neurotransmission in cocaine-treated rats, representing a novel therapeutic target.

Animals↗
PubMed2006

Transplant tolerance: converging on a moving target.

Enthusiasm for tolerance induction has been tempered by the realization that it is more difficult to achieve clinically than was predicted by experimental models. Unlike the view that the immune response to an allograft is ordered and thus predictable, we view alloimmunity as highly plastic and molded by previous and ongoing experiences with allogeneic and environmental antigens. This implies that an individual's response to an allograft changes over time and that responses of seemingly similar individuals may vary greatly. This variability highlights the need to develop assays for monitoring the recipient immune response as well as individualized methods for therapeutic immune modulation.

Animals↗
PubMed2005

Target-specific regulation of synaptic amplitudes in the neocortex.

In layers 2/3 in the rat visual cortex, glutamatergic synapses, between pyramidal neurons and GABAergic interneurons, show target-specific depression or facilitation. To study the mechanisms regulating these short-term synaptic modifications, we recorded from synaptically connected pyramidal neurons (presynaptic) and multipolar or bitufted interneurons (postsynaptic). Evoked AMPA receptor (AMPAR)- or NMDA receptor (NMDAR)-mediated EPSCs were pharmacologically isolated at these pyramidal-to-interneuron synapses while altering release probability (P(r)) by changing the extracellular Ca2+ concentration ([Ca2+]o). At the pyramidal-to-multipolar synapse, which shows paired-pulse depression, elevation of [Ca2+]o from physiological concentrations (2 mm) to 3 mm increased the amplitude of the initial AMPAR-mediated EPSC and enhanced paired-pulse depression. In contrast, the initial NMDAR-mediated EPSC did not change in amplitude with raised P(r) nor was paired-pulse depression altered. This lack of an increase of NMDAR-mediated currents is not a result of Ca2+-dependent effects on the NMDAR. Rather, at the pyramidal-to-multipolar synapse, raised P(r) increases the transient glutamate concentration at individual release sites, possibly reflecting multivesicular release. In contrast, at the pyramidal-to-bitufted synapse, which shows facilitation, AMPAR- and NMDAR-meditated EPSCs showed parallel increases in response to raised P(r). Thus, our results reveal differential recruitment of AMPA and NMDARs at depressing and facilitating synapses in layers 2/3 of the cortex and suggest that the mechanisms regulating dynamic aspects of synaptic transmission are target specific.

Animals↗
PubMed2005

[Molecular mechanisms in acute and chronic pain states].

BACKGROUND: Pain is a sense necessary for survival and has a complex neurobiological basis. In recent years a powerful battery of techniques has been developed to unravel the mechanisms by which painful stimuli are transduced and processed both in the acute and pathological state. MATERIAL AND ANALYSIS: We review the literature with special emphasis on recent discoveries regarding the molecular transduction mechanisms in nociceptors and novel molecular and cellular mechanisms underlying the spinal processing of painful stimuli. RESULTS AND INTERPRETATION: The mechanisms by which sensory neurons initiate hyperalgesia and touch-evoked pain (allodynia) have been addressed particularly successfully in recent studies. The rich variety of key molecular players that have emerged in physiological and pathophysiological pain states reflects the sophistication and uniqueness of this important sense. This is good news for both the pain scientist and the pain clinician since it increases the intellectual challenge and provides a plethora of targets for novel analgesics and treatments.

Acute Disease↗