Research themes My research is focused on how inhibitory changes in nerve tissues influence brain function, i.e. sensory coding, integration and behavioral expression. Apart from identifying the underlying mechanisms controling short- and long-term changes in inhibition, the consequences of theses changes are also studied in pathological conditions such as epilepsy and chronic pain. Some achievements are listed below:
• Gycinergic inhibition, and desinhibition in pain states Harvey RJ, Depner UB, Wassle H, Ahmadi S, Heindl C, Reinold H, Smart TG, Harvey K, Schutz B, Abo-Salem OM, Zimmer A, Poisbeau P, Welzl H, Wolfer DP, Betz H, Zeilhofer HU, Muller U. GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization. Science, 2004. 304(5672): p. 884-7. A collaborative article confirming that glycinergic disinhibition play a key role in inflammatory pain states. Briefly, PGE2 binds to EP2 receptors leading to an increased activity of PKA, phsophorylating alpha3 containing glycine receptors in layer I-II of the dorsal horn spinal cord. This action is responsible for the appearance of pain symptoms as demosnatrted with an alpha3 glycine receptor knock out mice which are insensitive to inflammatory pain. Rajalu M, Muller UC, Caley A, Harvey RJ, Poisbeau P. Plasticity of synaptic inhibition in mouse spinal cord lamina II neurons during early postnatal development and after inactivation of the glycine receptor alpha3 subunit gene. Eur J Neurosci, 2009. 30(12): p. 2284-92. • GABAergic inhibition, and desinhibition in pain states Keller AF, Coull JA, Chery N, Poisbeau P, De Koninck Y. Region-specific developmental specialization of GABA-glycine cosynapses in laminas I-II of the rat spinal dorsal horn. J Neurosci, 2001. 21(20): p. 7871-80. Characterization of the postnatal maturation of inhibitory synapses in the dorsal horn of the spinal cord. In addition to the demosnatration that mixed GABA/glycine are present, the article illustrate how theses synapses differentially mature between layer I and II. (work done by Florence Keller under my supervision / in collaboration with Yves de Koninck's group in Québec). Keller AF, Breton JD, Schlichter R, Poisbeau P. Production of 5alpha-reduced neurosteroids is developmentally regulated and shapes GABA(A) miniature IPSCs in lamina II of the spinal cord. J Neurosci, 2004. 24(4): p. 907-15. Poisbeau P, Patte-Mensah C, Keller AF, Barrot M, Breton JD, Luis-Delgado OE, Freund-Mercier MJ, Mensah-Nyagan AG, Schlichter R. Inflammatory pain upregulates spinal inhibition via endogenous neurosteroid production. J Neurosci, 2005. 25(50): p.11768-76. As previously shown during development (Keller et al, J Neurosci 2004), this article shows that endogenous neurosteroids shapes the efficacy of GABAergic inhibition in the spinal cord and limits the excitability associated with the expression of inflammatory pain symptoms. • Modulation by neurosteroids and preclinical interest in pain states (REVIEW ARTICLE) Schlichter R, Keller AF, De Roo M, Breton JD, Inquimbert P, and Poisbeau P. Fast nongenomic effects of steroids on synaptic transmission and role of endogenous neurosteroids in spinal pain pathways. J Mol Neurosci 2006, 28(1): p. 33-51. Vergnano AM, Schlichter R, Poisbeau P. PKC activation sets an upper limit to the functional plasticity of GABAergic transmission induced by endogenous neurosteroids. Eur J Neurosci, 2007. 26(5): p. 1173-82. A paper describing how modulation of GABAA receptors by neurosteroid depend on the intracellular phosophorylation states priori to the presence of neurosteroids. And conversely.... Benbouzid M, Pallage V, Rajalu M, Waltisperger E, Doridot S, Poisbeau P, Freund-Mercier MJ, Barrot M. Sciatic nerve cuffing in mice: a model of sustained neuropathic pain. Eur J Pain, 2008. 12(5): p. 591-9. Charlet A, Lasbennes F, Darbon P, Poisbeau P. Fast non-genomic effects of progesterone-derived neurosteroids on nociceptive thresholds and pain symptoms. Pain, 2008. 139(3): p. 603-9. Demonstration that progesterone-derived neurosteroids, such as allopreganolone, are potent analgesics and account for the progesterone-mediated pain reflief ! Zell V, Hanesch U, Poisbeau P, Anton F, Darbon P. Plasma glucocorticoids differentially modulate phasic and tonic GABA inhibition during early postnatal development in rat spinal lamina II. Neurosci Lett, 2014. 578: p. 39-43. Characterization of glucocorticoid impact on synaptic and extrasynaptic inhibition mediated by GABAA receptors. Zell V, Juif PE, Hanesch U, Poisbeau P, Anton F, Darbon P. Corticosterone analgesia is mediated by the spinal production of neuroactive metabolites that enhance GABAergic inhibitory transmission on dorsal horn rat neurons. Eur J Neurosci, 2015. 41(3): p. 390-7. (REVIEW ARTICLE) Poisbeau P, Keller AF, Aouad M, Kamoun N, Groyer G, Schumacher M. Analgesic strategies aimed at stimulating the endogenous production of allopregnanolone. Front Cell Neurosci 2014, 8,174. 4. Melchior M, Poisbeau P, Gaumond I, Marchand S. Insights into the Mechanisms and the Emergence of Sex-Differences in Pain. Neuroscience 2016, 338:63-80. • Modulation by oxytocin and preclinical interest in pain states Breton JD, Veinante P, Uhl-Bronner S, Vergnano AM, Freund-Mercier MJ, Schlichter R, Poisbeau P. Oxytocin-induced antinociception in the spinal cord is mediated by a subpopulation of glutamatergic neurons in lamina I-II which amplify GABAergic inhibition. Mol Pain, 2008. 4: p. 19. A study explaining how oxytocin receptor-mediated spinal analgesia is induced. Briefly, a subpopulation of excitatory interneurons in the superficial layer is oxytocin sensitive and spread their excitation to all GABAergic interneurons. This increase of the GABAergic inhibition result in a limitation of ascending "pain messages" and of pain symptoms in inflamamtory conditions. Breton JD, Poisbeau P, Darbon P. Antinociceptive action of oxytocin involves inhibition of potassium channel currents in lamina II neurons of the rat spinal cord. Mol Pain, 2009. 5: p. 63. A follow up of the previous article showing that general reduction of the excitability of spinal nociceptive neuron, together with the increase in synaptic inhibition mediated by GABAA receptors (Breton et al 2008), contributes to limit pain symptoms when present. Juif PE, Breton JD, Rajalu M, Charlet A, Goumon Y, Poisbeau P. Long-lasting spinal oxytocin analgesia is ensured by the stimulation of allopregnanolone synthesis which potentiates GABA(A) receptor-mediated synaptic inhibition. J Neurosci, 2013. 33(42): p. 16617-26. In addition to the network-driven fast action of oxytocin on GABAergic transmission in the spinal cord (Breton et al, Mol Pain 2008), oxytocin seems to stimulate the production of allopregnanolone thus providing a long-term reinforcement of neuronal inhibition in inflammatory pain states. Juif PE, Poisbeau P. Neurohormonal effects of oxytocin and vasopressin receptor agonists on spinal pain processing in male rats. Pain, 2013. 154(8): p. 1449-56. An important study demonstrating the dose-dependent analgesic/proalgesic effects of blood oxytocin and vasopressin. Eliava M*, Melchior M*, Knobloch-Bollmann HS*, Wahis J*, Da Silva Gouveia M, Tang, Y., Ciobanu AC, Triana del Rio R, Roth LC, Althammer F, Chavant V, Goumon Y, Gruber T, Petit-Demoulière N, Busnelli M, Chini B, Tan L, Mitre M, Froemke RC, Chao MV, Giese G, Sprengel R, Kuner R, Poisbeau P, Seeburg PH, Stoop R, Charlet A, Grinevich V. A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing. Neuron, 2016, 89(6):1291-304. Identification of a subpopulation of oxytocinergic neurons which coordinate the analgesic action at central (spinal cord) and peripheral sites. These neurons are limited in number (~30 parvocellular neurons) and located in the paraventricular nuclei. • Modulation by etifoxine and preclinical interest in pain states Schlichter R, Rybalchenko V, Poisbeau P, Verleye M, Gillardin J. Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine. Neuropharmacology, 2000. 39(9): p. 1523-35. The first demonstration that etifoxine, a non benzodiazepine anxiolytic, has a dual action on GABAA receptor-channels: 1) a direct action on the receptor as PAM and 2) an indirect action : after binding to the mitochondria, the compound stimulates the production of allopregnanolone, the most potent endogenous PAM for GABAA receptors! Aouad M, Charlet A, Rodeau JL, Poisbeau P. Reduction and prevention of vincristine-induced neuropathic pain symptoms by the non-benzodiazepine anxiolytic etifoxine are mediated by 3alpha-reduced neurosteroids. Pain, 2009. 147(1-3): p. 54-9. Etifoxine is a non-benzodiazpeine anxiolytics which act as a positive allosteric modulator (PAM) of GABAA receptors. It also stimulates the production of endogenous neurosteroids, among which allopregnanolone, th emost potent endogenous PAM. In this study, we show that a 5-day treatment is sufficient to alleviate neuropathic pain symptoms appearing after vincristine sulfate antitumoral chemotherapy; If given prior to vincristine sulfate, it prevents from the apparition of neuropathic pain symptoms. Aouad M, Petit-Demouliere N, Goumon Y, Poisbeau P. Etifoxine stimulates allopregnanolone synthesis in the spinal cord to produce analgesia in experimental mononeuropathy. Eur J Pain, 2014. 18(2): p. 258-68. Aouad M, Zell V, Juif PE, Lacaud A, Goumon Y, Darbon P, Lelievre V, Poisbeau P. Etifoxine analgesia in experimental monoarthritis: a combined action that protects spinal inhibition and limits central inflammatory processes. Pain, 2014. 155(2): p. 403-12. Juif PE, Melchior M, Poisbeau P. Characterization of the fast GABAergic inhibitory action of etifoxine during spinal nociceptive processing in male rats. Neuropharmacology, 2015. 91: p. 117-22.
Luis-Delgado OE, Barrot M, Rodeau JL, Schott G, Benbouzid M, Poisbeau P, Freund-Mercier MJ, Lasbennes F. Calibrated forceps: a sensitive and reliable tool for pain and analgesia studies. J Pain, 2006. 7(1): p. 32-9. Yalcin I, Charlet A, Freund-Mercier MJ, Barrot M, Poisbeau P. Differentiating thermal allodynia and hyperalgesia using dynamic hot and cold plate in rodents. J Pain, 2009. 10(7): p. 767-73. Charlet A, Rodeau JL, Poisbeau P. Poincare plot descriptors of heart rate variability as markers of persistent pain expression in freely moving rats. Physiol Behav, 2011. 104(5): p. 694-701. Charlet A, Rodeau JL, Poisbeau P. Radiotelemetric and symptomatic evaluation of pain in the rat after laparotomy: long-term benefits of perioperative ropivacaine care. J Pain, 2011. 12(2): p. 246-56. Yalcin I, Charlet A, Cordero-Erausquin M, Tessier LH, Picciotto MR, Schlichter R, Poisbeau P, Freund-Mercier MJ, Barrot M. Nociceptive thresholds are controlled through spinal beta2-subunit-containing nicotinic acetylcholine receptors. Pain, 2011. 152(9): p. 2131-7. Zeitler A, Kamoun N, Goyon S, Wahis J, Charlet A, Poisbeau P, Darbon P. Favouring inhibitory synaptic drive mediated by GABA(A) receptors in the basolateral nucleus of the amygdala efficiently reduces pain symptoms in neuropathic mice. Eur J Neurosci. 2016, 43(8):1082-8. Duval CZ, Goumon Y, Kemmel V, Kornmeier J, Dufour A, Andlauer O, Vidailhet P, Poisbeau P, Salvat E, Muller A, Mensah-Nyagan AG, Schmidt-Mutter C, Giersch A. Neurophysiological responses to unpleasant stimuli (acute electrical stimulations and emotional pictures) are increased in patients with schizophrenia. Sci Rep. 2016, 6:22542. Juif PE, Salio C, Zell V, Melchior M, Lacaud A, Petit-Demouliere N, Ferrini F, Darbon P, Hanesch U, Anton F, Merighi A, Lelièvre V, Poisbeau P. Peripheral and central alterations affecting spinal nociceptive processing and pain at adulthood in rats exposed to neonatal maternal deprivation. Eur J Neurosci. 2016, 44(3):1952-62. Our first published study using this model of neonatal maternal separation (NMS). Nociceptive hypersensitivity of NMS animals (also observed in human subject with premature birth) is explained by the overexpression of nociceptive-specific sodium channels.
Charlet A, Muller AH, Laux A, Kemmel V, Schweitzer A, Deloulme JC, Stuber D, Delalande F, Bianchi E, Van Dorsselaer A, Aunis D, Andrieux A, Poisbeau P, Goumon Y. Abnormal nociception and opiate sensitivity of STOP null mice exhibiting elevated levels of the endogenous alkaloid morphine. Mol Pain, 2010. 6: p. 96. Laux A, Muller AH, Miehe M, Dirrig-Grosch S, Deloulme JC, Delalande F, Stuber D, Sage D, Van Dorsselaer A, Poisbeau P, Aunis D, Goumon Y. Mapping of endogenous morphine-like compounds in the adult mouse brain: Evidence of their localization in astrocytes and GABAergic cells. J Comp Neurol, 2011. 519(12): p. 2390-416. Laux-Biehlmann A, Grafe N, Mouheiche J, Stuber D, Welters ID, Delalande F, Poisbeau P, Garnero P, Metz-Boutigue MH, Schneider F, Goumon Y. Comparison of serum and lithium-heparinate plasma for the accurate measurements of endogenous and exogenous morphine concentrations. Br J Clin Pharmacol, 2012. 74(2): p. 381-3. Laux A, Delalande F, Mouheiche J, Stuber D, Van Dorsselaer A, Bianchi E, Bezard E, Poisbeau P, Goumon Y. Localization of endogenous morphine-like compounds in the mouse spinal cord. J Comp Neurol, 2012. 520(7): p. 1547-61. Laux-Biehlmann A, Chung H, Mouheiche J, Veriepe J, Delalande F, Lamshoft M, Welters ID, Soldevila S, Bazin H, Lamarque L, Van Dorsselaer A, Poisbeau P, Schneider F, Goumon Y, Garnero P. Endogenous morphine-6-glucuronide (M6G) is present in the plasma of patients: validation of a specific anti-M6G antibody for clinical and basic research. Biofactors, 2014. 40(1): p. 113-20.
• Mechanisms silencing GABAA synapses Poisbeau P, Williams SR, Mody I. Silent GABAA synapses during flurazepam withdrawal are region-specific in the hippocampal formation. J Neurosci, 1997. 17(10): p. 3467-75. The article demostrates that neuronal hyper-excitability in the hippocampus after benzodiazpeine withdrawal is actually due to a transient silencing of GABAergic synapses. Mechanisms likely involves post-translational modifications instead of chloride homeostasis alterations.. Poisbeau P, Cheney MC, Browning MD, Mody I. Modulation of synaptic GABAA receptor function by PKA and PKC in adult hippocampal neurons. J Neurosci, 1999. 19(2): p. 674-83. The highly cited article is a follow-up of the precious one (Poisbeau et al, J Neurosci 1997) and suggests that the silencing of GABAergic synapses could be due to a region-specific regulation by protein kinases A and C. • Sensitivity of hippocampal GABAA synapses to benzodiazepine and neurosteroid in a model of temporal lobe epilepsy Leroy C*, Poisbeau P*, Keller AF, Nehlig A. Pharmacological plasticity of GABA(A) receptors at dentate gyrus synapses in a rat model of temporal lobe epilepsy. J Physiol, 2004. 557(Pt 2): p. 473-87. Demonstration that synaptic GABAA receptors are insensitive to benzodiazepine, but not to neurosteroids, in a model of temporal lobe epilepsy. The likely hypothesis points the role of a subunit composition change and the over-expression of alpha4-delta receptors.
• Control of neuro-endocrine cell excitability Poisbeau P, Trouslard J, Feltz P, Schlichter R. Calcium influx through neuronal-type nicotinic acetylcholine receptors present on the neuroendocrine cells of the porcine pars intermedia. Neuroendocrinology, 1994. 60(4): p. 378-88. Poisbeau P, Jo YH, Feltz P, Schlichter R. Electrophysiological characterization of non-NMDA glutamate receptors on cultured intermediate lobe cells of the rat pituitary. Neuroendocrinology, 1996. 64(2): p. 162-8. Poisbeau P, Rene F, Egles C, Felix JM, Feltz P, Schlichter R. Characterization of functional GABAergic synapses formed between rat hypothalamic neurons and pituitary intermediate lobe cells in coculture: Ca2+ dependence of spontaneous IPSCs. J Neurosci, 1996. 16(16): p. 4835-45. Using primary culture, we found that the action potential-independent inhibitory transmission (miniature) at newly-formed hypothalamo-hypophyseal GABAergic synapses is highly sensitive to extracellular calcium concentration changes. Rene F, Poisbeau P, Egles C, Schlichter R, Felix JM. Co-culture of hypothalamic neurons and melanotrope cells: a model to study synaptogenesis between central neurons and endocrine cells. Neuroscience, 1997. 76(1): p. 203-14. • Neurosteroid modulation of synaptic transmission mediated by GABAA receptors Poisbeau P, Feltz P, Schlichter R. Modulation of GABAA receptor-mediated IPSCs by neuroactive steroids in a rat hypothalamo-hypophyseal coculture model. J Physiol, 1997. 500 ( Pt 2): p. 475-85. The first demonstration that neurosteroids actually modulate GABAA receptor-mediated synaptic transmission. In particular, allopregnanolone-like compounds which are the most potent endogenous positive allosteric modulators of GABAA receptor-channels. Schlichter R, Rybalchenko V, Poisbeau P, Verleye M, Gillardin J. Modulation of GABAergic synaptic transmission by the non-benzodiazepine anxiolytic etifoxine. Neuropharmacology, 2000. 39(9): p. 1523-35. The first demonstration that etifoxine, a non benzodiazepine anxiolytic, has a dual action on GABAA receptor-channels: 1) a direct action on the receptor as PAM and 2) an indirect action : after binding to the mitochondria, the compound stimulates the production of allopregnanolone, the most potent endogenous PAM for GABAA receptors!
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