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See detailFunctional analysis of the F337C mutation in the CLCN1 gene associated with dominant myotonia congenita reveals an alteration of the macroscopic conductance and voltage dependence
Jehasse, Kevin ULiege; Jacquerie, Kathleen ULiege; de Froidmont, Alice ULiege et al

in Molecular Genetics and Genomic Medicine (2021)

Background: Myotonia congenita (MC) is a common channelopathy affecting skeletal muscle and which is due to pathogenic variants within the CLCN1 gene. Various alterations in the function of the channel ... [more ▼]

Background: Myotonia congenita (MC) is a common channelopathy affecting skeletal muscle and which is due to pathogenic variants within the CLCN1 gene. Various alterations in the function of the channel have been reported and we here illustrate a novel one. Methods: A patient presenting the symptoms of myotonia congenita was shown to bear a new heterozygous missense variant in exon 9 of the CLCN1 gene (c.1010 T > G, p.(Phe337Cys)). Confocal imaging and patch clamp recordings of transiently transfected HEK293 cells were used to functionally analyze the effect of this variant on channel properties. Results: Confocal imaging showed that the F337C mutant incorporated as well as the WT channel into the plasma membrane. However, in patch clamp, we observed a smaller conductance for F337C at −80 mV. We also found a marked reduction of the fast gating component in the mutant channels, as well as an overall reduced voltage dependence. Conclusion: To our knowledge, this is the first report of a mixed alteration in the biophysical properties of hClC-1 consisting of a reduced conductance at resting potential and an almost abolished voltage dependence.channel gating, CLCN1, microscopy, myotonia, patch clamp [less ▲]

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See detailThe atypical chemokine receptor ACKR3/CXCR7 is a broad-spectrum scavenger for opioid peptides.
Meyrath, Max Marc Roger ULiege; Szpakowska, Martyna; Zeiner, Julian et al

in Nature Communications (2020), 11(1), 3033

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7 ... [more ▼]

Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3's negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity. [less ▲]

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See detailOn the path to understanding pacemaking of dopaminergic neurons
Jehasse, Kevin ULiege; Massotte, Laurent ULiege; Hartmann, Sébastian et al

Poster (2020, May 22)

Despite many years of investigations by many researchers, the mechanism of pacemaking of midbrain dopaminergic (DA) neurons remains unknown. Several groups found that the Ih current, which is prominent in ... [more ▼]

Despite many years of investigations by many researchers, the mechanism of pacemaking of midbrain dopaminergic (DA) neurons remains unknown. Several groups found that the Ih current, which is prominent in a majority of these neurons, enhances pacemaking in a subgroup of DA neurons, but this is not its core mechanism. We and others have been able to rule out various types of Cav channels as pacemaking generators. In our hands, NALCN channels do not seem to contribute either, because the (admittedly non-selective) blocker Gd3+ does not reliably affect pacemaking of DA neurons at 100 µM, whereas it stops fast pacemaking of reticulata GABAergic neurons (Lutas et al., 2016). Because we know that slow pacemaking of DA neurons necessitates only a very small inward current (1-6 pA) (Khaliq and Bean, 2008), we tested the hypothesis that their pacemaking is due to many membrane proteins with a very low unitary conductance. To do this, we investigated the effect of 1-(2,4-xylyl) guanidinium (XG) on their firing. This compound had been shown to block a so-called gating pore current in pathological Nav1.4 channels (Sokolov et al., 2010). In the presence of synaptic blockers (including 1 µM sulpiride), XG completely stopped the firing of DA neurons in a concentration-dependent manner (IC50 was 485 µM, Hill coefficient was 1.28), suggesting a one-to-one interaction. The effect of XG was only weakly reversible, but the firing in the partially inhibited neurons (200-600 µM) remained extremely stable after superfusion of the drug, arguing against a toxic effect. The effect of XG was similar in young and adult rat DA neurons, and was also seen in mouse DA neurons (SH and JR). Because the commercially available XG salt is poorly water-soluble, we (RV and JFL) synthesized a much more soluble salt (XG-M) which yielded the same effect (IC50 was 427 µM). XG inhibited the firing of DA neurons without affecting their conductance and without inducing a hyperpolarization, contrary to D2 agonists. In addition, in the presence of XG, DA neurons could be induced to fire with a small amount of positive current (10 to 30 pA), and their action potential properties were unaffected by the drug. Finally, XG did not affect the pacemaking of fast GABAergic pacemakers. Using pacemaker clamp (imposing in voltage clamp the waveform of spontaneous firing), we isolated a small XG-sensitive inward current which operates from ~-60 to ~-20 mV, but is not seen at more hyperpolarized potentials, arguing against a gating pore current. Molecular biology experiments (BL and KJ) also ruled out an editing of mRNAs coding for the main voltage-dependent channels of these neurons in their S4 segments (this could have been the mechanism of a « physiological » gating pore). In ion substitution experiments, we found that the XG-sensitive current is carried by Na+ and Cl- ions, but not Ca2+ or K+ ions. Given these characteristics, we recently checked whether the dopamine transporter would be involved, since it had been shown to depolarize cultured DA neurons (Ingram et al., 2002). However, we recently ruled out this hypothesis. What could be the nature of this elusive XG-sensitive current? [less ▲]

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See detailL’expérimentation animale : toujours une nécessité pour la santé animale et humaine
Balthazart, Jacques ULiege; Blanpain, Cédric; Bureau, Fabrice ULiege et al

Article for general public (2019)

Le 1 juillet 2019, « Le Soir » publiait un article relatant la découverte par les chercheurs de l'UCLouvain d'une bactérie pouvant potentiellement contribuer à limiter les risques cardiovasculaires , l ... [more ▼]

Le 1 juillet 2019, « Le Soir » publiait un article relatant la découverte par les chercheurs de l'UCLouvain d'une bactérie pouvant potentiellement contribuer à limiter les risques cardiovasculaires , l'une des premières causes de décès en Belgique. Cet article soulignait l'importance de la recherche fondamentales et du passage nécessaire par l'expérimentation préclinique (animale) pour développer une application chez l’humain. En réaction, Solange T'Kint, administratrice de l'ASBL S.E.A. - Suppression des Expériences sur l'Animal-, publiait le 2 juillet dans « La Libre » un nouveau pamphlet contre l'expérimentation animale. Mme T Kint avait déjà lancé en aout 2018 une pétition attaquant la découverte3 d'un chercheur de l'ULB sur la dépendance aux drogues réalisée chez la souris , démontrant par là à quel point toute avancée médicale imputable à l'expérimentation animale lui est insupportable. Ici se trouve la réponse de Scientifiques qui pensent indispensable d’informer chacun-e- de manière rigoureuse et de ne jamais laisser diffuser de « fake news » sans réagir. [less ▲]

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See detailSubsaturation of the NMDAR glycine site allows the regulation of bursting activity in juvenile rat nigral dopamine neurons
Destreel, Geoffrey ULiege; Seutin, Vincent ULiege; Engel, Dominique ULiege

in European Journal of Neuroscience (2019), 50(9), 3454-3471

The activation of N-methyl-D-aspartate receptors (NMDARs) in substantia nigra pars compacta (SNc) dopamine (DA) cells is central to generate the bursting activity, a phasic signal linked to DA related ... [more ▼]

The activation of N-methyl-D-aspartate receptors (NMDARs) in substantia nigra pars compacta (SNc) dopamine (DA) cells is central to generate the bursting activity, a phasic signal linked to DA related behaviors via the change in postsynaptic DA release. NMDARs are recruited during excitatory synaptic transmission by glutamate release but the glycine site level of occupancy of these receptors during basal action potential-dependent activity is not known for SNc DA neurons. We explored NMDARdependent signals during exogenous applications of co-agonists in midbrain slices from juvenile rats. We found that both glycine and D-serine strengthened the NMDAR-dependent component of excitatory postsynaptic currents (EPSCs) in a concentration-dependent manner. EPSCs were also increased by endogenous glycine via the blockade of the glycine transport. The glycine site of NMDARs contributing to synaptic transmission is therefore subsaturated. The behaviorally relevant burst firing was more sensitive to exogenous D-serine and endogenous glycine than to exogenous glycine. The mechanisms regulating the availability of the co-agonists exert consequently a critical influence on the excitability of DA neurons via NMDARs. The modulation of the phasic firing in DA neurons by ambient NMDAR co-agonists may be important for nigral information processing and downstream motor-related behavior. [less ▲]

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See detailInvestigating the reciprocal relationships between locomotor sensitization to ethanol and PTSD-like clusters in DBA/2J mice.
Matonda Ma Nzuzi, ULiege; Didone, Vincent ULiege; Seutin, Vincent ULiege et al

in Behavioural Brain Research (2019)

BACKGROUND: Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are two conditions that co-occur frequently. The mechanistic explanations of this co-morbidity are still unclear. The goal ... [more ▼]

BACKGROUND: Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are two conditions that co-occur frequently. The mechanistic explanations of this co-morbidity are still unclear. The goal of this study was twofold. First to investigate whether PTSD reduces the threshold for the acquisition of ethanol sensitization in an animal model of PTSD. Then to investigate whether ethanol sensitization modulates the expression of PTSD. METHODS: 152 female inbred DBA/2 J mice were submitted to an inescapable footshock paradigm to induce a PTSD-like condition (PTSDLC) and to a paradigm of locomotor sensitization to ethanol. In a first experiment, mice were submitted to the PTSDLC and then repeatedly injected with either saline, 1 g/kg ethanol or 2 g/kg ethanol. Their sensitization to the locomotor stimulant effects of ethanol was then tested in an open field. In a second experiment, mice were first sensitized to the locomotor stimulant effects of ethanol and then tested for their behavioral response to PTSDLC. RESULTS: In the first experiment, PTSDLC failed to induce a significant locomotor sensitization at the subthreshold dose of 1 g/kg ethanol. However, with 2 g/kg ethanol, a stronger ethanol sensitization was observed in mice submitted to the footshock relative to the control group. In the second experiment, ethanol sensitization increased only some of the behavioral clusters of PTSDLC, namely the fear generalization in a new context. CONCLUSION: PTSDLC did not reduce the dose threshold for the acquisition of ethanol sensitization but strengthened the development of ethanol sensitization with effective doses. This suggests that PTSD might interact with one of the mechanisms underlying the development of alcohol sensitization. When the relationship between ethanol sensitization and PTSDLC is tested in the reverse direction, the present study only shows a significant effect of ethanol administration on the "sensitized fear" PTSD cluster. [less ▲]

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See detailEffect of Amphetamine on Ventral Tegmental Area Neurons in awake Rats
Delairesse, Charlotte ULiege; Koulchitsky, Stanislav ULiege; Seutin, Vincent ULiege

Poster (2018, December 18)

Amphetamine (AMPH) is an addictive psychostimulant targeting the dopamine system. But its effect on the neurons of this system is still unclear. Here, we studied the effects of amphetamine on the firing ... [more ▼]

Amphetamine (AMPH) is an addictive psychostimulant targeting the dopamine system. But its effect on the neurons of this system is still unclear. Here, we studied the effects of amphetamine on the firing rate of dopamine (DA) and non-dopamine neurons of the ventral tegmental area, a key structure in the reward circuit, of awake rats. Using wireless neural probes to investigate the electrical activity of the neurons in freely moving rats, we observed that acute injection of AMPH is followed by a decrease of firing rate of most of registered DA units. The remaining population of DA units either increased or did not significantly change their activity. At the same time, AMPH stimulated the locomotor activity and induced a stereotypic behavior. (FR) L'amphétamine (AMPH) est un psychostimulant addictif visant le système dopaminergique. Cependant, ses effets sur les neurones de ce système sont nébuleux. Nous étudions les effets de l'AMPH sur la fréquence de décharge des neurones dopaminergiques et non dopaminergique de l'aire tegmentale ventrale, une structure clef du circuit de la récompense, de rats éveillés. En utilisant un système d'électrodes sans fil pour étudier l'activité électrique des neurones de rats libres de leurs mouvements, nous avons observer que l'injection aiguë d'AMPH est suivie d'une diminution de la fréquence de décharge de la majorité des neurones dopaminergiques enregistrés. Le reste des neurones dopaminergique présentaient une activité augmentée ou qui ne subissait pas de changement significatif. En même temps, l'AMPh stimule l'activité locomotrice et induit un comportement stéréotypé. [less ▲]

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See detailExpérimentation animale: la recette d'une polémique scientifique
Muraille, Eric; de kerchove, Alban; Muylkens, Benoit et al

Article for general public (2018)

La majorité du grand public accepte l’expérimentation animale à condition que celle-ci contribue à l’amélioration de la santé humaine et qu’aucune autre alternative n’existe. En face, les opposants ... [more ▼]

La majorité du grand public accepte l’expérimentation animale à condition que celle-ci contribue à l’amélioration de la santé humaine et qu’aucune autre alternative n’existe. En face, les opposants décrédibilisent la recherche et stigmatise une profession à des fins idéologiques. Relevé de leurs arguments. [less ▲]

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See detailLa souris, le patient, et le faux expert. Décryptage d'une mystification.
Bakker, Julie ULiege; Balthazart, Jacques ULiege; Baron, Frédéric ULiege et al

Article for general public (2018)

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les ... [more ▼]

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les contrôles qui y sont associés induisent de nombreuses contraintes pratiques, des charges administratives et des coûts financiers importants que les chercheurs seraient certainement heureux d'éviter s'il existait une alternative à l'expérimentation animale. [less ▲]

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See detailL'expérimentation animale ne se fait pas en dehors de tout contrôle (OPINION)
Muraille, Eric; de Kerchove d'Exaerde, Alban; Blanpain, Cedric et al

Article for general public (2018)

Proposer de réduire l'expérimentation animale pour raisons morales est louable. Mais ce choix de société ne doit pas être vendu au citoyen en lui laissant croire que la recherche conserverait la même ... [more ▼]

Proposer de réduire l'expérimentation animale pour raisons morales est louable. Mais ce choix de société ne doit pas être vendu au citoyen en lui laissant croire que la recherche conserverait la même qualité ou en serait améliorée. [less ▲]

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See detailAnalyse détaillée de la seconde version de l’avant-projet de Code du bien-être animal wallon. Lecture commentée au 21/03/2018 du Chapitre 8 (Expérimentation animale)
Drion, Pierre ULiege; Corhay, Albert ULiege; Haubruge, Eric ULiege et al

Report (2018)

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par ... [more ▼]

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par les décrets du Gouvernement wallon). Certains éléments sont repris tels quels de la Directive 2010/63. Cela est nécessaire car la Directive européenne en tant que telle n’a pas de force obligatoire en Belgique. Elle doit être transcrite par un instrument législatif (avant, la Loi de 1984 et ses modifications, aujourd’hui, le projet de code pour la Région wallonne). Certains aspects semblent flous, mais renvoient à des dispositions que le Gouvernement doit encore prendre (au travers d’arrêtés du Gouvernement wallon, comme le faisaient avant les nombreux arrêtés royaux et du gouvernement qui réglementent la matière). Les arrêtés d’exécution devront obligatoirement tenir compte de la Directive européenne et s’inspirer de dispositions actuellement en vigueur. [less ▲]

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See detailL’expérimentation animale reste indispensable (OPINION)
Amorim, Christiani; Andris, Fabienne; Arckens, Lut et al

Article for general public (2017)

Trop fréquemment, l’expérimentation animale est présentée comme une pratique archaïque. Elle a bien changé. Et 100 % des patients traités le sont grâce aux concepts et techniques développés grâce à elle.

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See detailModulation of NMDA receptor mediated excitatory synaptic currents in dopamine neurons of the substantia nigra.
Destreel, Geoffrey ULiege; Seutin, Vincent ULiege; Engel, Dominique ULiege

Poster (2017, November 08)

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) exhibit two main firing modes, spontaneous single action potential (AP) firing and bursting. The amount of DA released by these neurons in ... [more ▼]

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) exhibit two main firing modes, spontaneous single action potential (AP) firing and bursting. The amount of DA released by these neurons in target areas depends on the presynaptic AP firing pattern and is essential to modulate several aspects of behavior such as the control of movement. Bursting activity is mediated by excitatory afferents and specifically by the activation of NMDA receptors (NMDARs). However, the level of activation of NMDARs at these synapses during spontaneous synaptic activity is unknown. We assessed the occupancy of the glycine binding sites of the NMDAR by testing the effects of coagonists and by blocking the uptake of glycine on spontaneous excitatory postsynaptic currents (sEPSCs) in DA neurons of the SNc. [less ▲]

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See detailAvant-projet de décret relatif au Code wallon du Bien-être des animaux Lecture commentée au 04 juillet 2017 des chap. 4, 8, 11
Drion, Pierre ULiege; Seutin, Vincent ULiege; Balthazart, Jacques ULiege et al

Report (2017)

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par ... [more ▼]

La compétence « bien-être animal », auparavant fédérale, a été régionalisée en juillet 2014. Ce projet de code vise à remplacer les dispositions légales en vigueur (la Loi de 1984 telle que modifiée par les décrets du Gouvernement wallon). Certains éléments sont repris tels quels de la Directive 2010/63. Cela est nécessaire car la Directive européenne en tant que telle n’a pas de force obligatoire en Belgique. Elle doit être transcrite par un instrument législatif (avant, la Loi de 1984, aujourd’hui, le projet de code). Certains aspects semblent flous, mais renvoient à des dispositions que le Gouvernement doit encore prendre (au travers d’arrêtés du Gouvernement wallon, comme le faisaient avant les nombreux arrêtés royaux et du gouvernement qui réglementent la matière). Les arrêtés d’exécution devront obligatoirement tenir compte de la directive européenne et s’inspirer de dispositions actuellement en vigueur. [less ▲]

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See detailModulation of NMDA receptor mediated excitatory synaptic currents in dopamine neurons of the substantia nigra
Destreel, Geoffrey ULiege; Seutin, Vincent ULiege; Engel, Dominique ULiege

Poster (2017, May 17)

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) exhibit two main firing modes, spontaneous single action potential (AP) firing and bursting. The amount of DA released by these neurons in ... [more ▼]

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) exhibit two main firing modes, spontaneous single action potential (AP) firing and bursting. The amount of DA released by these neurons in target areas depends on the presynaptic AP firing pattern and is essential to modulate several aspects of behavior such as the control of movement. Bursting activity is mediated by excitatory afferents and specifically by the activation of NMDA receptors (NMDARs). However, the level of activation of NMDARs at these synapses during spontaneous synaptic activity is unknown. We assessed the occupancy of the glycine binding sites of the NMDAR by testing the effects of coagonists and by blocking the uptake of glycine on spontaneous excitatory postsynaptic currents (sEPSCs) in DA neurons of the SNc. Parasagittal midbrain slices (300 – 350 µm thickness) were cut from the brains 16- to 26- days old Wistar rats using a vibratome. Whole-cell recordings were made using warm (~35C°) standard artificial cerebrospinal fluid. sEPSCs were pharmacologically isolated and recorded at +40 and -70 mV. A large NMDAR-sEPSC component was present at +40 mV as revealed by the application of 50 µM D-AP5 (n=8, P < 0.001). At -70 mV, D-AP5 had no effect on the EPSC, as expected (n=7, P = 0.52). The mean amplitude of the average NMDAR sEPSC measured at +40 mV increased significantly from 8.6 ± 0.8 pA in control conditions to 10.9 ± 1.0 pA during bath application of 300 μM glycine (n=10, P < 0.001). We also investigated the effect of D-serine, the other coagonist at the NMDAR glycine site. The mean NMDAR EPSC amplitude measured at +40 mV showed a tendency toward larger values, from 6.8 ± 0.8 pA in control conditions to 8.8 ± 1.1 pA in the presence of 100 µM D-serine (n=4). Blockade of the glycine transporter-1 (GlyT1) significantly increased the mean amplitude of NMDAR sEPSCs measured at +40 mV from 7.1 ± 0.5 pA in control conditions to 10.5 ± 0.8 pA in the presence of 5 μM NFPS (n=8, P < 0.001). At -70 mV, NFPS had no effect on the AMPAR-sEPSC component, as expected (n=8, P = 0.23). In conclusion, our results indicate that the NMDAR glycine sites are not saturated by glycine and D-serine during sEPSCs in control conditions. [less ▲]

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See detailModulation of NMDA receptor mediated excitatory synaptic currents in dopamine neurons of the substantia nigra.
Destreel, Geoffrey ULiege; Seutin, Vincent ULiege; Engel, Dominique ULiege

Poster (2017, March 17)

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) exhibit two main firing modes, spontaneous single action potential (AP) firing and bursting. The amount of DA released by these neurons in ... [more ▼]

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) exhibit two main firing modes, spontaneous single action potential (AP) firing and bursting. The amount of DA released by these neurons in target areas depends on the presynaptic AP firing pattern and is essential to modulate several aspects of behavior such as the control of movement. Bursting activity is mediated by excitatory afferents and specifically by the activation of NMDA receptors (NMDARs). However, the level of activation of NMDARs at these synapses during spontaneous synaptic activity is unknown. We assessed the occupancy of the glycine binding sites of the NMDAR by testing the effects of coagonists and by blocking the uptake of glycine on spontaneous excitatory postsynaptic currents (sEPSCs) in DA neurons of the SNc. Parasagittal midbrain slices (300 – 350 µm thickness) were cut from the brains 16- to 26- days old Wistar rats using a vibratome. Whole-cell recordings were made using warm (~35C°) standard artificial cerebrospinal fluid. sEPSCs were pharmacologically isolated and recorded at +40 and -70 mV. A large NMDAR-sEPSC component was present at +40 mV as revealed by the application of 50 µM D-AP5 (n=8, P < 0.001). At -70 mV, D-AP5 had no effect on the EPSC, as expected (n=7, P = 0.52). The mean amplitude of the average NMDAR sEPSC measured at +40 mV increased significantly from 8.6 ± 0.8 pA in control conditions to 10.9 ± 1.0 pA during bath application of 300 μM glycine (n=10, P < 0.001). We also investigated the effect of D-serine, the other coagonist at the NMDAR glycine site. The mean NMDAR EPSC amplitude measured at +40 mV showed a tendency toward larger values, from 6.8 ± 0.8 pA in control conditions to 8.8 ± 1.1 pA in the presence of 100 µM D-serine (n=4). Blockade of the glycine transporter-1 (GlyT1) significantly increased the mean amplitude of NMDAR sEPSCs measured at +40 mV from 7.1 ± 0.5 pA in control conditions to 10.5 ± 0.8 pA in the presence of 5 μM NFPS (n=8, P < 0.001). At -70 mV, NFPS had no effect on the AMPAR-sEPSC component, as expected (n=8, P = 0.23). In conclusion, our results indicate that the NMDAR glycine sites are not saturated by glycine and D-serine during sEPSCs in control conditions. [less ▲]

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See detailEffect of electrode morphology on the frquency spectrum of local field potentials in the rat ventral tegmental area
Delairesse, Charlotte ULiege; Seutin, Vincent ULiege; Koulchitsky, Stanislav ULiege

Poster (2016, November 14)

Implantable microelectrode arrays for chronic neural recordings receive an attention by a number of research groups investigating ensemble spike activity and local field potentials. Due to that interest ... [more ▼]

Implantable microelectrode arrays for chronic neural recordings receive an attention by a number of research groups investigating ensemble spike activity and local field potentials. Due to that interest, various types of arrays have been developed. In the present study we compared the LFP signals recorded from the ventral tegmental area (VTA) of freely moving male Wistar rats using the two types of arrays: microelectrode microwire arrays, and silicon-based planar probes. Our choice was based on the difference in the geometry of these two array types. The microwire electrodes have a three-dimensional recording surface around their tips. This allows them to receive the signal from the diverse brain regions. In contrast, the electrode contacts of the planar probe are patterned on one side of the silicon shaft (often named top-side, in contrast to the other, back-side). This configuration mainly allows registering the signal from the top-side of the shaft, while the signal from the back-side gets attenuated. Microwire arrays used in this study consisted of 8 sharpened platinum iridium wires, coated with parylene-C, except for the tip allowing the recording (Alpha Omega GmbH, Israel). Planar probes (ATLAS Neuroengineering, Belgium) had 16 iridium oxide electrode contacts implemented in the 4 silicon shafts, 4 electrode contacts per shaft. The recording was performed using a wireless system (W-Basic-System, Multi Channel Systems MCS GmbH, Germany). The probes were implanted in two orientations: top-side facing the midline, and top-side facing the lateral plane of the brain. For verification of the recording area the rats were anaesthetized and perfused with 4% paraformaldehyde containing 1 % of Gadovist. The brains were removed from the skull and placed in Fomblin for MRI scanning (9.4 Tesla MRI DirectDrive VNMRS, Agilent Technologies, Palo Alto, CA). Frequency spectra of LFP recorded by the microwire arrays, and by the planar probes oriented to the lateral plane of the brain contained a prominent peak in the theta range (6-8 Hz). In contrast, the signal registered using the planar probes oriented to the midline lacked such a peak and was more heterogeneous. We attribute the observed difference to the geometry of the recording platforms. [less ▲]

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See detailInteractions between calcium channels and SK channels in midbrain dopamine neurons and their impact on pacemaker regularity: Contrasting roles of N- and L-type channels.
de Vrind, V.; Scuvée-Moreau, Jacqueline ULiege; Drion, Guillaume ULiege et al

in European Journal of Pharmacology (2016), 788

Although small-conductance Ca2+-activated K+ (SK) channels and various types of voltage-gated Ca2+ (Cav) channels have been described in midbrain dopaminergic neurons, the nature of their interactions is ... [more ▼]

Although small-conductance Ca2+-activated K+ (SK) channels and various types of voltage-gated Ca2+ (Cav) channels have been described in midbrain dopaminergic neurons, the nature of their interactions is unclear. More particularly, the role of various Cav channel types in either promoting irregularity of firing (by generating an inward current during SK channel blockade) or promoting regularity of firing (by providing the source of Ca2+ for the activation of SK channels) has not been systematically explored. We addressed this question using intracellular and extracellular recordings from substantia nigra, pars compacta (SNc), dopaminergic neurons in rat midbrain slices. Neurons were pharmacologically isolated from their differences. When examining the ability of various Cav channel blockers to inhibit the SK-mediated afterhyperpolarization (AHP), we found that only the N-type Cav channel blocker ω-conotoxin-GVIA was able to reduce the apamin-sensitive AHP, but only partially (~40%). Specific blockers of L, P/Q, T or R channels had no effect on this AHP. Combining ω-conotoxin-GVIA and other specific blockers did not yield greater block and even the broad Cav blocker Cd2+ induced a submaximal (~75%) effect. Extracellular recordings examining firing regularity yielded congruent results: none of the specific blockers was able to increase firing irregularity to the extent that the specific SK blocker apamin did. The irregularity of firing observed with apamin could only be reversed by blocking L-type Ca2+ channels. Thus various sources of Ca2+ appear to be required for SK channel activation in SNc neurons (some of them still unidentified), ensuring robustness of pacemaking regularity. [less ▲]

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See detailModulation of NMDA receptor mediated excitatory synaptic currents in dopamine neurons of the substantia nigra.
Destreel, Geoffrey ULiege; Seutin, Vincent ULiege; Engel, Dominique ULiege

Poster (2016, April 22)

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) exhibit two main firing modes, spontaneous single action potential (AP) firing and bursting. The amount of DA released by these neurons in ... [more ▼]

Dopamine (DA) neurons of the substantia nigra pars compacta (SNc) exhibit two main firing modes, spontaneous single action potential (AP) firing and bursting. The amount of DA released by these neurons in target areas depends on the presynaptic AP firing pattern and is essential to modulate several aspects of behavior such as the control of movement. Bursting activity is mediated by excitatory afferents and specifically by the activation of NMDA receptors (NMDARs). However, the level of activation of NMDARs at these synapses during spontaneous synaptic activity is unknown. We assessed the occupancy of the glycine binding sites of the NMDAR by testing the effects of coagonists and by blocking the uptake of glycine on spontaneous excitatory postsynaptic currents (sEPSCs) in DA neurons of the SNc. Parasagittal midbrain slices (300 – 350 µm thickness) were cut from the brains 16- to 26- days old Wistar rats using a vibratome. Whole-cell recordings were made using warm (~35C°) standard artificial cerebrospinal fluid. sEPSCs were pharmacologically isolated and recorded at +40 and -70 mV. A large NMDAR-sEPSC component was present at +40 mV as revealed by the application of 50 µM D-AP5 (n=8, P < 0.001). At -70 mV, D-AP5 had no effect on the EPSC, as expected (n=7, P = 0.52). The mean amplitude of the average NMDAR sEPSC measured at +40 mV increased significantly from 8.6 ± 0.8 pA in control conditions to 10.9 ± 1.0 pA during bath application of 300 μM glycine (n=10, P < 0.001). We also investigated the effect of D-serine, the other coagonist at the NMDAR glycine site. The mean NMDAR EPSC amplitude measured at +40 mV showed a tendency toward larger values, from 6.8 ± 0.8 pA in control conditions to 8.8 ± 1.1 pA in the presence of 100 µM D-serine (n=4). Blockade of the glycine transporter-1 (GlyT1) significantly increased the mean amplitude of NMDAR sEPSCs measured at +40 mV from 7.1 ± 0.5 pA in control conditions to 10.5 ± 0.8 pA in the presence of 5 μM NFPS (n=8, P < 0.001). At -70 mV, NFPS had no effect on the AMPAR-sEPSC component, as expected (n=8, P = 0.23). In conclusion, our results indicate that the NMDAR glycine sites are not saturated by glycine and D-serine during sEPSCs in control conditions. [less ▲]

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