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See detailGlycine Receptor α2 Subunit Activation Promotes Cortical Interneuron Migration
Avila Macaya, Ariel Salvatore ULg; Vidal, Pia M; Dear, T Neil et al

in Cell Reports (2013)

Glycine receptors (GlyRs) are detected in the developing CNS before synaptogenesis, but their function remains elusive. This study demonstrates that functional GlyRs are expressed by embryonic cortical ... [more ▼]

Glycine receptors (GlyRs) are detected in the developing CNS before synaptogenesis, but their function remains elusive. This study demonstrates that functional GlyRs are expressed by embryonic cortical interneurons in vivo. Furthermore, genetic disruption of these receptors leads to interneuron migration defects. We discovered that extrasynaptic activation of GlyRs containing the α2 subunit in cortical interneurons by endogenous glycine activates voltage-gated calcium channels and promotes calcium influx, which further modulates actomyosin contractility to fine-tune nuclear translocation during migration. Taken together, our data highlight the molecular events triggered by GlyR α2 activation that control cortical tangential migration during embryogenesis. [less ▲]

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See detailStudy of the interaction of antiplasmodial strychnine derivatives with the glycine receptor
Philippe, Geneviève ULg; Nguyen, Laurent ULg; Angenot, Luc ULg et al

in European Journal of Pharmacology (2006), 530(1-2), 15-22

Strychnos icaja Baill. (Loganiaccae) is a liana found in Central Africa known to be an arrow and ordeal poison but also used by traditional medicine to treat malaria. Recently, many dimeric or trimeric ... [more ▼]

Strychnos icaja Baill. (Loganiaccae) is a liana found in Central Africa known to be an arrow and ordeal poison but also used by traditional medicine to treat malaria. Recently, many dimeric or trimeric indolomonoterpenic alkaloids with antiplasmodial properties have been isolated from its rootbark. Since these alkaloids are derivatives of strychnine, it was important, in view of their potential use as antimalarial drugs, to assess their possible convulsant strychnine-like properties. In that regard, their interaction with the strychnine-sensitive glycine receptor was investigated by whole-cell patch-clamp recordings on glycine-gated currents in mouse spinal cord neurons in culture and by [H-3]strychnine competition assays on membranes from adult rat spinal cord. These experiments were carried out on sungucine (leading compound of the chemical class) and on the antiplasmodial strychnogucine B (dimeric) and strychnohexamine (trimeric). In comparison with strychnine, all compounds interact with a very poor efficacy and only at concentrations > I mu M with both [H-3]strychnine binding and glycine-gated currents. Furthermore, the effects of strychnine and protostrychnine, a monomeric alkaloid (without antiplasmodial activity) also isolated from S. icaja and differing from strychnine only by a cycle opening, were compared in the same way. The weak interaction of protostrychnine confirms the importance of the G cycle ring structure in strychnine for its binding to the glycine receptor and its antagonist properties. (c) 2005 Elsevier B.V. All rights reserved. [less ▲]

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See detailLarge group teaching: the distance learning solution?
Pasleau, Françoise ULg; Doseray, Patrick; Fairon, Nicolas ULg et al

Poster (2005, June)

Problem-based learning has been introduced at the University of Liège for four years now. The medical library was committed with the organisation of different activities (60 hours/2 years), starting with ... [more ▼]

Problem-based learning has been introduced at the University of Liège for four years now. The medical library was committed with the organisation of different activities (60 hours/2 years), starting with the control of basic computer litteracy, continuing with an analysis of the structure of the different document types used for scientific communication as well as the discovery of both traditional and electronic medical libraries, to end with guidelines for information retrieval. Such courses requested new approaches and several difficulties had to be taken into consideration including : 1. The transfer of skills rather than kowledge. Some theoretical bases have to be taught before practicing. But the students mostly need to be challenged with different situations requesting different approaches of litterature searching. 2. The course is given before the students feel the need of it. The librarians enconter the students during the first semester of the second year before the students are asked to search the medical litterature to build their own knowledge about clinical matters. 3. The absence of motivation. Second year medical students are focused on major courses in basic and preclinical sciences. 4. Large group teaching (n ≥ 300). All the sections of the medical Faculty are concerned. 5. Inadequate logistic support. Small sized computer rooms do not allow the organization of very many parallel hand-on sessions. 6. Insufficient teaching staffs. Distance learning tools were used to develope online activities complementary to face to face teaching. They are focused on practice. Links to the theory are provided but only when they are indispensable. Many quizzes are also proposed in order to trigger critical mind and auto-evaluation. By January 2005, a first cycle will be completed from the beginning of the course to the final examination. We plan to survey students from every section in order to evaluate the impact of this new teaching strategy. Their observations will be reported as well as our conclusions and suggestions for possible improvements. [less ▲]

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See detailDevelopmental regulation of beta-carboline-induced inhibition of glycine-evoked responses depends on glycine receptor beta subunit expression
Mangin, Jean-Marie; Nguyen, Laurent ULg; Gougnard, Catherine et al

in Molecular Pharmacology (2005), 67(5), 1783-1796

In this work, we show that beta-carbolines, which are known negative allosteric modulators of GABA A receptors, inhibit glycine-induced currents of embryonic mouse spinal cord and hippocampal neurons. In ... [more ▼]

In this work, we show that beta-carbolines, which are known negative allosteric modulators of GABA A receptors, inhibit glycine-induced currents of embryonic mouse spinal cord and hippocampal neurons. In both cell types, beta-carboline-induced inhibition of glycine receptor (GlyR)-mediated responses decreases with time in culture. Single-channel recordings show that the major conductance levels of GlyR unitary currents shifts from high levels (>= 50 pS) in 2 to 3 days in vitro (DIV) neurons to low levels (< 50 pS) in 11 to 14 DIV neurons, assessing the replacement of functional homomeric GlyR by heteromeric GlyR. In cultured spinal cord neurons, the disappearance of beta-carboline inhibition of glycine responses and high conductance levels is almost complete in mature neurons, whereas a weaker decrease in beta-carboline-evoked glycine response inhibition and high conductance level proportion is observed in hippocampal neurons. To confirm the hypothesis that the decreased sensitivity of GlyR to beta-carbolines depends on beta subunit expression, Chinese hamster ovary cells were permanently transfected either with GlyR alpha 2 subunit alone or in combination with GlyR beta subunit. Single-channel recordings revealed that the major conductance levels shifted from high levels (>= 50 pS) in GlyR-alpha 2-transfected cells to low levels (< 50 pS) in GlyR-alpha 2-containing cells. Consistently, both picrotoxinand beta-carboline-induced inhibition of glycine-gated currents were significantly decreased in GlyR-alpha 2-transfected cells compared with GlyR-alpha 2-containing cells. In summary, we demonstrate that the incorporation of beta subunits in GlyRs confers resistance not only to picrotoxin but also to beta-carbolineinduced inhibition. Furthermore, we also provide evidence that hippocampal neurons undergo in vitro a partial maturation process of their GlyR-mediated responses. [less ▲]

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See detailPeripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression
Hans, Grégory ULg; Wislet, Sabine ULg; Lallemend, François et al

in Biochemical Pharmacology (2005), 69(5), 819-830

Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising ... [more ▼]

Some synthetic ligands of the peripheral-type benzodiazepine receptor (PBR), an 18 kDa protein of the outer mitochondrial membrane, are cytotoxic for several tumor cell lines and arise as promising chemotherapeutic candidates. However, conflicting results were reported regarding the actual effect of these drugs on cellular survival ranging from protection to toxicity. Moreover, the concentrations needed to observe such a toxicity were usually high, far above the affinity range for their receptor, hence questioning its specificity. In the present study, we have shown that micromolar concentrations of FGIN-1-27 And Ro 5-4864, two chemically unrelated PBR ligands are toxic for both PBR-expressing SK-N-BE neuroblastoma cells and PBR-deficient Jurkat lymphoma cells. We have thereby demonstrated that the cytotoxicity of these drugs is unrelated to their PBR-binding activity. Moreover, Ro 54864-induced cell death differed strikingly between both cell types, being apoptotic in Jurkat cells while necrotic in SK-N-BE cells. Again, this did not seem to be related to PBR expression since Ro 5-4864-induced death of PBR-transfected Jurkat cells remained apoptotic. Taken together, our results show that PBR is unlikely to mediate all the effects of these PBR ligands. They however confirm that some of these ligands are very effective cytotoxic drugs towards various cancer cells, even for reputed chemoresistant tumors such as neuroblastoma, and, surprisingly, also for PBR-lacking tumor cells. (C) 2004 Elsevier Inc. All rights reserved. [less ▲]

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See detailbeta-carbolines induce apoptosis in cultured cerebellar granule neurons via the mitochondrial pathway
Hans, Grégory ULg; Malgrange, Brigitte ULg; Lallemend, François et al

in Neuropharmacology (2005), 48(1), 105-117

N-Butyl-beta-carboline-3-carboxylate (betaCCB) is, together with 2-methyl-norharmanium and 2,9-dimethylnorharmanium ions, an endogenously occurring beta-carboline. Due to their structural similarities ... [more ▼]

N-Butyl-beta-carboline-3-carboxylate (betaCCB) is, together with 2-methyl-norharmanium and 2,9-dimethylnorharmanium ions, an endogenously occurring beta-carboline. Due to their structural similarities with the synthetic neurotoxin 1-methy14-phenyl-1,2,3,6-tetrahydropyridine (MPTP), harman and norharman compounds have been proposed to be involved in the pathogenesis of Parkinson's disease. While also structurally related, betaCCB has received much less interest in that respect although we had previously demonstrated that it induces the apoptotic cell death of cultured cerebellar granule neurons (CGNs). Herein, we have investigated the molecular events leading to CGN apoptosis upon betaCCB treatment. We first demonstrated that betaCCB-induced apoptosis occurs in neurons only, most likely as a consequence of a specific neuronal uptake as shown using binding/uptake experiments. Then we observed that, in betaCCB-treated CGNs, caspases 9, 3 and 8 were successively activated, suegesing an activation of the mitochondrial pathway. Consistently, betaCCB also induced the release from the mitochondrial intermembrane space of two pro-apoptotic factors. i.e. cytochrome c and apotptosis inducing factor (AIF). Interestingly, no mitochondrial membrane depolarisation was associated with this release. suggesting a mitochondrial permeability transition pore-independent mechanism. The absence of any neuroprotective effect provided by two mPTP inhibitors. i.e. cyclosporine A and bongkrekic acid. further supported this hypothesis. Together. these results show that betaCCB is specifically taken up by neuronal cells where it triggers a specific permeabilization of the outer mitochondrial membrane and a subsequent apoptotic cell death. (C) 2004 Elsevier Ltd. All rights reserved. [less ▲]

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See detailPlasticity of cultured mesenchymal stem cells: switch from nestin-positive to excitable neuron-like phenotype.
Wislet-Gendebien, Sabine ULg; Hans, Grégory ULg; Leprince, Pierre ULg et al

in Stem Cells (2005), 23(3), 392-402

Bone marrow mesenchymal stem cells (MSCs) can differentiate into several types of mesenchymal cells, including osteocytes, chondrocytes, and adipocytes, but, under appropriate experimental conditions, can ... [more ▼]

Bone marrow mesenchymal stem cells (MSCs) can differentiate into several types of mesenchymal cells, including osteocytes, chondrocytes, and adipocytes, but, under appropriate experimental conditions, can also differentiate into nonmesenchymal cells--for instance, neural cells. These observations have raised interest in the possible use of MSCs in cell therapy strategies for various neurological disorders. In the study reported here, we addressed the question of in vitro differentiation of MSCs into functional neurons. First, we demonstrate that when they are co-cultured with cerebellar granule neurons, adult MSCs can express neuronal markers. Two factors are needed for the emergence of neuronal differentiation of the MSCs: the first one is nestin expression by MSCs (nestin is a marker for the responsive character of MSCs to extrinsic signals), and the second one is a direct cell-cell interaction between neural cells and MSCs that allows the integration of these extrinsic signals. Three different approaches suggest that neural phenotypes arise from MSCs by a differentiation rather than a cell fusion process, although this last phenomenon can also coexist. The expression of several genes--including sox, pax, notch, delta, frizzled, and erbB--was analyzed by quantitative reverse transcription polymerase chain reaction (RT-PCR) in order to further characterize the nestin-positive phenotype compared to the nestin-negative one. An overexpression of sox2, sox10, pax6, fzd, erbB2, and erbB4 is found in nestin-positive MSCs. Finally, electrophysiological analyses demonstrate that MSC-derived neuron-like cells can fire single-action potentials and respond to several neurotransmitters such as GABA, glycine, and glutamate. We conclude that nestin-positive MSCs can differentiate in vitro into excitable neuron-like cells. [less ▲]

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See detailStriatal PSA-NCAM(+) precursor cells from the newborn rat express functional glycine receptors
Nguyen, Laurent ULg; Malgrange, Brigitte ULg; Breuskin, Ingrid ULg et al

in Neuroreport (2004), 15(4), 583-587

Immunocytochemical analysis showed that ionotropic glycine receptors are expressed in neurogenic progenitors purified from the newborn rat striatum and expressing the polysialylated form of the neural ... [more ▼]

Immunocytochemical analysis showed that ionotropic glycine receptors are expressed in neurogenic progenitors purified from the newborn rat striatum and expressing the polysialylated form of the neural cell adhesion molecule, both in vitro and in situ. To ascertain whether glycine receptors were functional in vitro, whole-cell patch-clamp recordings demonstrated that glycine triggers inward strychnine-sensitive currents in the majority of these cells. Moreover, we found that glycine receptors expressed by these neurogenic progenitors display intermediate electrophysiological characteristics between those of glycine receptors expressed by neural stem cells and by mature interneurons from the rat striatum. Altogether, the present data show that functional strychnine-sensitive glycine receptors are expressed in neurogenic progenitors purified from the newborn rat striatum. [less ▲]

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See detailKinetic properties of the alpha(2) homo-oligomeric glycine receptor impairs a proper synaptic functioning
Mangin, J. A.; Baloul, M.; de Carvalho, L. P. et al

in Journal of Physiology-London (2003), 553(2), 369-386

Ionotropic glycine receptors (GlyRs) are present in the central nervous system well before the establishment of synaptic contacts. Immature nerve cells are known, at least in the spinal cord, to express ... [more ▼]

Ionotropic glycine receptors (GlyRs) are present in the central nervous system well before the establishment of synaptic contacts. Immature nerve cells are known, at least in the spinal cord, to express alpha(2) homomeric GlyRs, the properties of which are relatively unknown compared to those of the adult synaptic form of the GlyR (mainly alpha(1)/beta heteromeres). Here, the kinetics properties of GlyRs at the single-channel level have been recorded in real-time by means of the patch-clamp technique in the outside-out configuration coupled with an ultra-fast flow application system (< 100 µs). Recordings were performed on chinese hamster ovary (CHO) cells stably transfected with the a, GlyR subunit. We show that the onset, the relaxation and the desensitisation of α(2) homomeric GlyR-mediated currents are slower by one or two orders of magnitude compared to synaptic mature GlyRs and to other ligand-gated ionotropic channels involved in fast synaptic transmission. First latency analysis performed on single GlyR channels revealed that their slow activation time course was due to delayed openings. When synaptic release of glycine was mimicked (1 mM glycine; 1 ms pulse duration), the opening probability of α(2) homomeric GlyRs was low (P-o ≈ 0.1) when compared to mature synaptic GlyRs (P-o = 0.9). This low P-o is likely to be a direct consequence of the relatively slow activation kinetics of α(2) homomeric GlyRs when compared to the activation kinetics of mature α(1)/β GlyRs. Such slow kinetics suggest that embryonic α(2) homomeric GlyRs cannot be activated by fast neurotransmitter release at mature synapses but rather could be suited for a non-synaptic paracrine-like release of agonist, which is known to occur in the embryo. [less ▲]

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See detailSubstance P protects spiral ganglion neurons from apoptosis via PKC-Ca2+-MAPK/ERK pathways
Lallemend, François; Lefèbvre, Philippe ULg; Hans, Grégory ULg et al

in Journal of Neurochemistry (2003), 87(2), 508-521

In the current study, we have investigated the ability of substance P (SP) to protect 3-day-old (P3) rat spiral ganglion neurons (SGNs) from trophic factor deprivation (TFD)-induced cell death. The ... [more ▼]

In the current study, we have investigated the ability of substance P (SP) to protect 3-day-old (P3) rat spiral ganglion neurons (SGNs) from trophic factor deprivation (TFD)-induced cell death. The presence of SP high affinity neurokinin-1 receptor (NK1) transcripts was detected in the spiral ganglion and the NK1 protein localized to SGNs both ex vivo and in vitro. Treatment with SP increased cytoplasmic Ca2+ in SGNs, further arguing for the presence of functional NK1 on these neurons. Both SP and the agonist [Sar(9), Met(O-2)(11)]-SP significantly decreased SGN cell death induced by TFD, with no effect on neurite outgrowth. The survival promoting effect of SP was blocked by the NK1 antagonist, WIN51708. Both pan-caspase inhibitor BOC-D-FMK and SP treatments markedly reduced activation of caspases and DNA fragmentation in trophic factor deprived-neurons. The neuroprotective action of SP was antagonised by specific inhibitors of second messengers, including 1.2-bis-(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM) to chelate cytosolic Ca2+, the protein kinase C (PKC) inhibitors bisindolylmaleimide I, Go6976 and LY333531 and the MAPK/ERK inhibitor U0126. In contrast, nifedipine, a specific inhibitor of L-type Ca2+ channel, and LY294002, a phosphatidylinositol-3-OH kinase (PI3K) inhibitor, had no effect on SP trophic support of SGNs. Moreover, activation of endogenous PKC by 4beta-phorbol 12-myristate 13-acetate (PMA) also reduced the loss of trophic factor-deprived SGNs. Thus, NK1 expressed by SGNs transmit a survival-promoting regulatory signal during TFD-induced SGN cell death via pathways involving PKC activation, Ca2+ signalling and MAPK/ERK activation, which can be accounted for by an inhibition of caspase activation. [less ▲]

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See detailChemical inhibitors of cyclin-dependent kinases control proliferation, apoptosis and differentiation of oligodendroglial cells
Nguyen, Laurent ULg; Malgrange, Brigitte ULg; Rocher, Véronique et al

in International Journal of Developmental Neuroscience (2003), 21(6), 321-326

Since cyclin-dependent kinases (Cdks) and their endogenous inhibitors (Cdkis) play an essential role as regulators of cell cycle withdrawal and onset of differentiation within oligodendroglial cells, we ... [more ▼]

Since cyclin-dependent kinases (Cdks) and their endogenous inhibitors (Cdkis) play an essential role as regulators of cell cycle withdrawal and onset of differentiation within oligodendroglial cells, we assessed here the effects of exogenous chemical Cdk inhibitors (CKIs) on cultured rat cortical oligodendrocyte progenitor cells (OPCs). We showed that purine derivatives and especially roscovitine strongly inhibited OPCs proliferation. In the presence of mitogenic signals, roscovitine synergized with thyroid hormone to stimulate oligodendrocyte differentiation. Roscovitine also prevented oligodendroglial apoptosis induced by growth factor deprivation. We thus demonstrated that small molecular weight chemical CKIs have important effects on crucial events of oligodendroglial development in vitro. This might open prospects for using these apparently well tolerated agents in remyelination strategies. (C) 2003 ISDN. Published by Elsevier Ltd. All rights reserved. [less ▲]

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See detailUntangling the functional potential of PSA-NCAM-expressing cells in CNS development and brain repair strategies
Nguyen, Laurent ULg; Rigo, Jean-Michel; Malgrange, Brigitte ULg et al

in Current Medicinal Chemistry (2003), 10(20), 2185-2196

Central nervous system (CNS) neural stem cells (NSCs), which are mostly defined by their ability to self-renew and to generate the three main cell lineages of the CNS, were isolated from discrete regions ... [more ▼]

Central nervous system (CNS) neural stem cells (NSCs), which are mostly defined by their ability to self-renew and to generate the three main cell lineages of the CNS, were isolated from discrete regions of the adult mammalian CNS including the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus in the hippocampus. At early stages of CNS cell fate determination, NSCs give rise to progenitors that express the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). PSA-NCAM(+) cells persist in adult brain regions where neuronal plasticity and sustained formation of new neurons occur. PSA-NCAM, has been shown to be involved in the regulation of CNS myelination as well as in changes of cell morphology that are necessary for motility, axonal guidance, synapse formation, and functional plasticity in the CNS. Although being preferentially committed to a restricted either glial or neuronal fate, cultured PSA-NCAM(+) progenitors do preserve a relative degree of multipotentiality. Considering that PSA-NCAM(+) cells can be neatly used for brain repair purposes, there is much interest for studying signaling factors regulating their development. With this regard, it is noteworthy that neurotransmitters, which belong to the micro-environment of neural cells in vivo, regulate morphogenetic events preceding synaptogenesis such as cell proliferation, migration, differentiation and death. Consistently, several ionotropic but also G-protein-coupled neurotransmitter receptors were found to be expressed in CNS embryonic and postnatal progenitors. In the present review, we outlined the ins and outs of PSA-NCAM(+) cells addressing to what extent our understanding of extrinsic and in particular neurotransmitter-mediated signaling in these CNS precursor cells might represent a new leading track to develop alternative strategies to stimulate brain repair. [less ▲]

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See detailAutocrine/paracrine activation of the GABA(A) receptor inhibits the proliferation of neurogenic polysialylated neural cell adhesion molecule-positive (PSA-NCAM+) precursor cells from postnatal striatum.
Nguyen, Laurent ULg; Malgrange, Brigitte ULg; Breuskin, Ingrid ULg et al

in Journal of Neuroscience (2003), 23(8), 3278-94

GABA and its type A receptor (GABA(A)R) are present in the immature CNS and may function as growth-regulatory signals during the development of embryonic neural precursor cells. In the present study, on ... [more ▼]

GABA and its type A receptor (GABA(A)R) are present in the immature CNS and may function as growth-regulatory signals during the development of embryonic neural precursor cells. In the present study, on the basis of their isopycnic properties in a buoyant density gradient, we developed an isolation procedure that allowed us to purify proliferative neural precursor cells from early postnatal rat striatum, which expressed the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). These postnatal striatal PSA-NCAM+ cells were shown to proliferate in the presence of epidermal growth factor (EGF) and formed spheres that preferentially generated neurons in vitro. We demonstrated that PSA-NCAM+ neuronal precursors from postnatal striatum expressed GABA(A)R subunits in vitro and in situ. GABA elicited chloride currents in PSA-NCAM+ cells by activation of functional GABA(A)R that displayed a typical pharmacological profile. GABA(A)R activation in PSA-NCAM+ cells triggered a complex intracellular signaling combining a tonic inhibition of the mitogen-activated protein kinase cascade and an increase of intracellular calcium concentration by opening of voltage-gated calcium channels. We observed that the activation of GABA(A)R in PSA-NCAM+ neuronal precursors from postnatal striatum inhibited cell cycle progression both in neurospheres and in organotypic slices. Furthermore, postnatal PSA-NCAM+ striatal cells synthesized and released GABA, thus creating an autocrine/paracrine mechanism that controls their proliferation. We showed that EGF modulated this autocrine/paracrine loop by decreasing GABA production in PSA-NCAM+ cells. This demonstration of GABA synthesis and GABA(A)R function in striatal PSA-NCAM+ cells may shed new light on the understanding of key extrinsic cues that regulate the developmental potential of postnatal neuronal precursors in the CNS. [less ▲]

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See detailIdentification of factors that maintain mammalian outer hair cells in adult organ of Corti explants
Malgrange, Brigitte ULg; Rigo, Jean-Michel; Coucke, Paul et al

in Hearing Research (2002), 170(1-2), 48-58

Both outer hair cells (OHCs) and inner hair cells (IHCs) survive and mature in 3 days old rat organ of Corti explants cultured for I month in a minimal essential medium. In contrast. under the same ... [more ▼]

Both outer hair cells (OHCs) and inner hair cells (IHCs) survive and mature in 3 days old rat organ of Corti explants cultured for I month in a minimal essential medium. In contrast. under the same culture conditions, only IHCs survive in explants from adult guinea pig organ of Corti while many of the OHCs are lost within the first 48 It. Hair cell Count,, show OHCs loss to be greater in the lower portion (i.e. middle turn) of the cochlea than Lit the apex. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) indicates that there is DNA damage in adult OHCs, within 8 h of explantation. Treatment of the adult organ of Corti explants with either actinomycin D (10(-7) M) or cycloheximide (10(-6) M) prevents most OHC losses . According to these results apoptosis may be the mechanism of OHC loss in adult organ of Corti explants, Stable membrane potentials recorded from the OHCs in both uncultured and actinomycin D-treated organ of Corti explants cultured for 72 h demonstrate the functional integrity of these hair cells. OHC losses in the adult guinea pig, organ of Corti cultures can also be prevented by treatment with several of the growth factors tested. i.e. acidic fibroblast growth factor (aFGF), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), transforming growth factor-beta1 (TGF-beta1). and glial cell-derived neurotrophic factor (GDNF). The results of this study suggest that growth factor therapy may be applicable to the treatment of some hearing disorders. (C) 2002 Elsevier Science B.V. All rights reserved. [less ▲]

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See detailThe anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents
Rigo, Jean-Michel; Hans, Grégory ULg; Nguyen, Laurent ULg et al

in British Journal of Pharmacology (2002), 136(5), 659-672

1 In this study in vitro and in vivo approaches were combined in order to investigate if the anti-epileptic mechanism(s) of action of levetiracetam (LEV; Keppra(R)) may involve modulation of inhibitory ... [more ▼]

1 In this study in vitro and in vivo approaches were combined in order to investigate if the anti-epileptic mechanism(s) of action of levetiracetam (LEV; Keppra(R)) may involve modulation of inhibitory neurotransmission. 2 GABA- and glycine-gated currents were studied in vitro using whole-cell patch-clamp techniques applied on cultured cerebellar granule, hippocampal and spinal neurons. Protection against clonic convulsions was assessed in vivo in sound-susceptible mice. The effect of LEV was compared with reference anti-epileptic drugs (AEDs): carbamazepine, phenytoin, valproate, clonazepam, phenobarbital and ethosuximide. 3 LEV contrasted the reference AEDs by an absence of any direct effect on glycine-gated currents. At high concentrations, beyond therapeutic relevance, it induced a small reduction in the peak amplitude and a prolongation of the decay phase of GABA-gated currents. A similar action on GABA-elicited currents was observed with the reference AEDs, except ethosuximide. 4 These minor direct effects contrasted with a potent ability of LEV (EC50 = 1-10 muM) to reverse the inhibitory effects of the negative allosteric modulators zinc and beta-carbolines on both GABA(A) and glycine receptor-mediated responses. 5 Clonazepam, phenobarbital and valproate showed a similar ability to reverse the inhibition of beta-carbolines on GABA-gated currents. Blockade of zinc inhibition of GABA responses was observed with clonazepam and ethosuximide. Phenytoin was the only AED together with LEV that inhibited the antagonism of zinc on glycine-gated currents and only clonazepam and phenobarbital inhibited the action of DMCM. 6 LEV (17 mg kg(-1)) produced a potent suppression of sound-induced clonic convulsions in mice. This protective effect was significantly abolished by co-administration of the beta-carboline FG 7142, from a dose of 5 mg kg(-1). In contrast, the benzodiazepine receptor antagonist flumazenil (up to 10 mg kg(-1)) was without any effect on the protection afforded by LEV. 7 The results of the present study suggest that a novel ability to oppose the action of negative modulators on the two main inhibitory ionotropic receptors may be of relevance for the anti-epileptic mechanism(s) of action of LEV. [less ▲]

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See detailFunctional glycine receptors are expressed by postnatal nestin-positive neural stem/progenitor cells
Nguyen, Laurent ULg; Malgrange, Brigitte ULg; Belachew, Shibeshih ULg et al

in European Journal of Neuroscience (2002), 15(8), 1299-1305

Multipotent neural stem and progenitor cells (NS/PCs) are well-established cell subpopulations occurring in the developing, and also in the mature mammalian nervous systems. Trophic and transcription ... [more ▼]

Multipotent neural stem and progenitor cells (NS/PCs) are well-established cell subpopulations occurring in the developing, and also in the mature mammalian nervous systems. Trophic and transcription factors are currently the main signals known to influence the development and the commitment of NS/PCs and their progeny. However, recent studies suggest that neurotransmitters could also contribute to neural development. In that respect, rodent-cultured embryonic NS/PCs have been reported to express functional neurotransmitter receptors. No similar investigation has, however, been made in postnatal and/or in adult rodent brain stem cells. In this study, using RT-PCR and immunocytochemical methods, we show that alpha(1) -, alpha(2) - and beta-subunit mRNAs and alpha-subunit proteins of the glycine ionotropic receptor are expressed by 80.5 +/- 0.9% of postnatal rat striatum-derived, nestin-positive cells within cultured neurospheres. Whole-cell patch-clamp experiments further demonstrated that glycine triggers in 33.5% of these cells currents that can be reversibly blocked by strychnine and picrotoxin. This demonstrates that NS/PCs express functional glycine receptors, the consequence(s) of their activation remaining unknown. [less ▲]

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See detailProliferative generation of mammalian auditory hair cells in culture
Malgrange, Brigitte ULg; Belachew, Shibeshih ULg; Thiry, Marc ULg et al

in Mechanisms of Development (2002), 112(1-2), 79-88

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See detailNeurotransmitters as Early Signals for Central Nervous System Development
Nguyen, Laurent ULg; Rigo, Jean-Michel; Rocher, Véronique et al

in Cell & Tissue Research (2001), 305(2), 187-202

During brain ontogenesis, the temporal and spatial generation of the different types of neuronal and glial cells from precursors occurs as a sequence of successive progenitor stages whose proliferation ... [more ▼]

During brain ontogenesis, the temporal and spatial generation of the different types of neuronal and glial cells from precursors occurs as a sequence of successive progenitor stages whose proliferation, survival and cell-fate choice are controlled by environmental and cellular regulatory molecules. Neurotransmitters belong to the chemical microenvironment of neural cells, even at the earliest stages of brain development. It is now established that specific neurotransmitter receptors are present on progenitor cells of the developing central nervous system and could play, during neural development, a role that has remained unsuspected until recently. The present review focuses on the occurrence of neurotransmitters and their corresponding ligand-gated ion channel receptors in immature cells, including neural stem cells of specific embryonic and neonatal brain regions. We summarize in vitro and in vivo data arguing that neurotransmitters could regulate morphogenetic events such as proliferation, growth, migration, differentiation and survival of neural precursor cells. The understanding of neurotransmitter function during early neural maturation could lead to the development of pharmacological tools aimed at improving adult brain repair strategies. [less ▲]

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See detailGlycine Triggers an Intracellular Calcium Influx in Oligodendrocyte Progenitor Cells Which Is Mediated by the Activation of Both the Ionotropic Glycine Receptor and Na+-Dependent Transporters
Belachew, Shibeshih ULg; Malgrange, Brigitte ULg; Rigo, Jean-Michel et al

in European Journal of Neuroscience (2000), 12(6), 1924-30

Using fluo-3 calcium imaging, we demonstrate that glycine induces an increase in intracellular calcium concentration ([Ca2+]i) in cortical oligodendrocyte progenitor (OP) cells. This effect results from a ... [more ▼]

Using fluo-3 calcium imaging, we demonstrate that glycine induces an increase in intracellular calcium concentration ([Ca2+]i) in cortical oligodendrocyte progenitor (OP) cells. This effect results from a calcium entry through voltage-gated calcium channels (VGCC), as it is observed only in OP cells expressing such channels, and it is abolished either by removal of calcium from the extracellular medium or by application of an L-type VGCC blocker. Glycine-triggered Ca2+ influx in OP cells actually results from an initial depolarization that is the consequence of the activation of both the ionotropic glycine receptor (GlyR) and Na+-dependent transporters, most probably the glycine transporters 1 (GLYT1) and/or 2 (GLYT2) which are colocalized in these cells. Through this GlyR- and transporter-mediated effect on OP intrcellular calcium concentration [Ca2+]i, glycine released by neurons may, as well as other neurotransmitters, serve as a signal between neurons and OP during development. [less ▲]

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See detailNeurotransmitter-Mediated Regulation of Cns Myelination: A Review
Belachew, Shibeshih ULg; Rogister, Bernard ULg; Rigo, Jean-Michel et al

in Acta Neurologica Belgica (1999), 99(1), 21-31

In addition to treatments aimed at preventing or limiting damage to myelin and oligodendrocytes, there is a crucial need for repair strategies in human demyelinating disorders. There is increasing ... [more ▼]

In addition to treatments aimed at preventing or limiting damage to myelin and oligodendrocytes, there is a crucial need for repair strategies in human demyelinating disorders. There is increasing evidence that besides growth factors, neurotransmitters can regulate different steps of the oligodendrogliogenesis. The present review on neurotransmitter receptor expression and function in the oligodendrocyte lineage emphasizes the concept that in this lineage cell proliferation and differentiation can be controlled through the modulation of the functional state of channel proteins and receptors, such as the delayed K+ rectifier, the AMPA/kainate, dopamine or muscarinic receptors, and, most likely, others yet to be found. We anticipate that a better understanding of the neurotransmitter-mediated neuronal oligodendroglial communication network opens prospects in the field of central nervous system (CNS) myelin repair, allowing the recruitment of the myelinating machinery that is known to remain present but quiescent in the CNS of multiple sclerosis patients. [less ▲]

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