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Co-agonists regulation of NMDAR in the developing and mature brain - Jean-Pierre Mothet

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Watching at the "D" side: D-amino acids and their significance in neurobiology
June 05 -June

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Co-agonists regulation of NMDAR in the developing and mature brain - Jean-Pierre Mothet

  1. 1. Jean-Pierre MOTHET, Ph.D Lab ‘Gliotransmisssion and Synaptopathies’ CNRS UMR7286 - Universite Aix Marseille Marseille, France Watching at the "D" side: D-amino acids and their significance in neurobiology Lake Como School of Advanced Studies , 5-9 June 2016 Co-agonists regulation of NMDAR in the developing and mature brain
  2. 2. Objectives of the lecture -Brief overview of NMDA receptors and D-serine metabolism -Roles of glycine and D-serine in gatting different pools of NMDA receptors -Roles of d-serine and glycine at NMDA receptors are controlled by synaptic actvity -Roles of d-serine is synapse specific and developmentally regulated -Neuromodulatory systems imprint D-serine/glycine functions
  3. 3. How brain communication operates?.... Graham Johnson, Boulder, Colorado …at chemical synapses Peter Clevestig – www.dez3d.com
  4. 4. Death- promoting Survival- promoting Normal physiological levels Pathological high levels Pathological low levels NMDA receptors activity The NMDA receptors: key regulators of cellular fates
  5. 5. The NMDA receptors: a complex family ! >48 possible combinations!!!
  6. 6. NMDA receptors are located at synaptic and extrasynaptic sites Ronald S. Petralia (2012) The Scientific World Journal
  7. 7. NMDA receptor: an unique receptor Gly A Model proposed by Johnson & Ascher (1987) and by Kleckner & Dingledine (1988) And widely accepted until…. Johnson and Ascher (1987) Nature; Kleckner and Dingledine (1988) Science; Danyzs and Parsons (1999) Pharmacol. Rev Martineau et al. (2006). TINS
  8. 8. D-serine, a non-essential metabolic amino acid with essential brain functions Gly Hippocampus: Mothet et al. (2000) Yang et al. (2003) Jungaud et al. (2006) Mothet et al. (2006) Zhang et al. (2008) Basu et al. (2009) Henneberger et al. (2010) Papouin et al. (2012) Rosenberg et al. (2012) Balu et al. (2013) Sultan et al. (2015) Le Bail et al. (2015) Hypothalamus: Panatier et al. (2006) Cerebral cortex Fossat et al. (2012) Meunier et al. (2015) Amygdala Li et al. (2013) Anterior cingulate cortex: Ren et al. (2006) Nucleus accumbens Curcio et al. (2013) Retina: Stevens et al. (2003, 2010) Lamas et al. (2007) Gustafson et al. (2007) Martineau et al. (2006) TINS
  9. 9. D-serine metabolism in the brain Glucose Pyruvate Glycine L-serine DAAO TCA cycle D-serine SR lactate BloodstreamDiet GABA,Glu,Gln + ATP Asp Astrocyte Energy for neurons NOS Arg Cit + NO Inhibition Stimulation Martineau et al. (2006). TINS C
  10. 10. Contribution of astrocytes to D-serine and glycine synaptic disposition
  11. 11. Probing the nature of the coagonist(s) for synaptic NMDA receptors D-ser but not glycine is a major endogenous coagonist for synaptic NMDARs for CA3-CA1 synapses D-ser astrocyte Postsynaptic neuron glutamatergic terminal RgDAAO Gly astrocyte Postsynaptic neuron glutamatergic terminal Glycine oxydase
  12. 12. Pharmacological dissection of synaptic subunits NMDA receptors composition Synaptic NMDA receptors are predominantly formed of GluN2A In 2-3 months old
  13. 13. Tonic activation of extrasynaptic NMDA receptors in hippocampal neurons Glycine but not D-serine controls extrasynaptic NMDAR-mediated tonic currents Meur K L et al. (2007) J Physiol
  14. 14. NMDAR and long term synaptic plasticity Ca2+ Ca2+ NMDA LTD Sustained activation of NMDAR Ca2+ Ca2+ LTP NMDA Malenka (1994) Cell LTD: Long Term Depression LTP: Long Term Potentiation LTD and LTP are cellular models of memory
  15. 15. Collingridge et al. (2004) Nat Rev Neurosci Differential role of synaptic and extrasynaptic NMDAR in long term synaptic plasticity
  16. 16. Contribution of synaptic and extrasynaptic NMDARs to LTP? Only synaptic NMDARs (gated by D-serine) are necessary for the inudction of hippocampal LTP
  17. 17. Contribution of synaptic and extrasynaptic NMDARs to LTD? Both extrasynaptic and synaptic NMDARs are necessary for the induction of hippocampal LTD
  18. 18. Neuronal D-serine and glycine regulate NMDA receptor-dependent synaptic activity….via the Asc-1 transporter Rosenberg et al. (2013) J. Neurosci.
  19. 19. Model 2: Neuronal D-serine (and glycine) are released through ASC-1 and modulate synaptic NMDARs Model 1: Glial D-serine is released by exocytosis and modulates synaptic NMDARs while glycine gates extrasynaptic NMDARS Two different models of NMDA receptors regulation by D-serine and glycine
  20. 20. Henneberger et al., (2010) Nature Astrocytic D-serine regulates synaptic plasticity Are Games over???.................
  21. 21. Benneyworth et al. (2012) Cell Mol Neurobiol Astrocyte- versus neuron-selective conditional null mutations of serine racemase
  22. 22. Benneyworth et al. (2012) Cell Mol Neurobiol LTP at the Schaffer collateral–CA1 synapses in the hippocampus is suppressed in nSRCKO but not in aSRCKO mice Astrocyte- versus neuron-selective conditional null mutations of serine racemase
  23. 23. Identity of Endogenous NMDAR Glycine Site Agonist in Amygdala Is Determined by Synaptic Activity Level Li et al. (2013) Nat Comm
  24. 24. Identity of Endogenous NMDAR Glycine Site Agonist in Amygdala Is Determined by Synaptic Activity Level Li et al. (2013) Nat Comm
  25. 25. Identity of Endogenous NMDAR Glycine Site Agonist in Amygdala Is Determined by Synaptic Activity Level Li et al. (2013) Nat Comm
  26. 26. NMDA receptor activation is impaired in nucleus accumbens slices from cocaine–treated rats. Curcio L et al. Brain 2013;136:1216-1230
  27. 27. D-serine biosynthesis/catabolism is altered in the nucleus accumbens of cocaine-treated rats. Curcio L et al. Brain 2013;136:1216-1230
  28. 28. Regulation of NMDA receptors function in the hippocampus 1. Could we generalize what has been found at excitatory CA3-CA1 synapses to all excitatory synapses in the hippocampus? 2. When during postnatal development of the brain D-serine and glycine enter into function?
  29. 29. Effect of RgDAAO and BsGO on IO curves in CA1 and DG in adult rrats (2-3 months) C A B Control RgDAAO fNMDA PFV CA1 2 mV 5 ms 0.2 mV 20 ms BsGO Control RgDAAO BsGO fNMDA PFV DG D 2 mV 5 ms 0.2 mV 20 ms D-ser astrocyte Postsynaptic neuron glutamatergic terminal RgDAAO Gly astrocyte Postsynaptic neuron glutamatergic terminal BsGO Stim Recordings in CA1 area Rec Stim Recordings in DG area Rec Le Bail et al.PNAS 2015 Relative contribution of D-serine and glycine to NMDA receptors activation at mature synapses in the hippocampus
  30. 30. Le Bail et al.PNAS 2015 Relative contribution of D-serine and glycine to NMDA receptors activation at mature synapses in the hippocampus
  31. 31. Synaptic transmission and LTP at the mPP-DG synapses in SR−/− mice Basu et al (2009) Mol Psychiatry LTP but not basal synaptic transmission is impaired at the mPP-DG synapses in SR−/− mice Balu DT et al. PNAS 2013;110:E2400-E2409 Stim Rec
  32. 32. CA1 vs DG segregation of the co-agonist identity and NMDARs subunits compostion (NR2A) (NR2B) Zinc : antagonist of NR2A (or GluN2A) Ro25-6981 : antagonist of NR2B (or GluN2B)
  33. 33. GluN2 subunits composition of NMDARs at mature SC-CA1 and mPP-DG synapses Ro25-6981 used at 2-4 µM Zinc in tricine used at 250-750 nM Le Bail et al.PNAS 2015
  34. 34. Immature synapse Mature synapse GluN2B GluN2A Experience-driven maturation Developmental switch in GluN2 subunits composition GluN2A GluN2B
  35. 35. Regional and developmental switch in GluN2 subunit composition and coagonists levels Le Bail et al.PNAS 2015 Collaboration with Silvia Sacchi & Loredano Pollegioni
  36. 36. The identity of the coagonist at SC-CA1 synapses during postnatal development? Le Bail et al.PNAS 2015
  37. 37. Pfizer Merck Serono Solvay Pharm Merck, Sharp & Dohme MGI Pharma Merck Co. Sunovion Sacchi et al. (2012) Curr. Pharm. Design D-amino acid oxidase: a target of interest
  38. 38. Regional and developmental functions of D-amino acid oxidase Le Bail et al.PNAS 2015
  39. 39. Developmental contribution of astrocyte to D-serine and glycine synaptic functions Proper astrocyte-neuron coupling is necessary for D-serine and glycine functions Le Bail et al.PNAS 2015
  40. 40. Relative contribution of co-agonists in NMDAR-dependent synaptic plasticity Le Bail et al.PNAS 2015
  41. 41. Neuromodulatory systems and D-serine
  42. 42. The DAergic system controls the levels of D-serine in the mPFC Tanahashi (2012) Br. J Pharmacol
  43. 43. The cannabinoid system contribute to astroglial Ca2+-signalling and control of synaptic plasticity in the neocortex Rasooli-Nejad et al. (2014) Philos Trans R Soc Lond B Biol Sci. Xu & Chen (2015) The Neuroscientist
  44. 44. Cannabinoid receptors control the Ca2+-dependent release of ATP and D-serine from glia in the neocortex Rasooli-Nejad et al. (2014) Philos Trans R Soc Lond B Biol Sci.
  45. 45. López-Hidalgo M, Salgado-Puga K, Alvarado-Martínez R, Medina AC, Prado-Alcalá RA, et al. (2012) Nicotine Uses Neuron-Glia Communication to Enhance Hippocampal Synaptic Transmission and Long-term Memory. PLoS ONE 7(11): e49998. doi:10.1371/journal.pone.0049998 Nicotine potention of synaptic transmission depends on glial cell activity
  46. 46. López-Hidalgo M, Salgado-Puga K, Alvarado-Martínez R, Medina AC, Prado-Alcalá RA, et al. (2012) Nicotine Uses Neuron-Glia Communication to Enhance Hippocampal Synaptic Transmission and Long-term Memory. PLoS ONE 7(11): e49998. doi:10.1371/journal.pone.004999 Glial D-serine is necessary for nicotine potentiation of synaptic transmission
  47. 47. Serine racemase and D-serine mediated NMDARS synaptic responses are altered in α7 nAChRs KO mice Lin et al (2014) Neurobiology of Disease Mouse PFC slices (8-10 weeks)
  48. 48. Singh et al. (2013) Cell signalling Nictotinic acetylcholine receptors regulate the function and expression of serine racemase PC-12 and 1321N1 cells
  49. 49. Takata et al. (2011) J. Neurosci. In vivo stimulation of the nucleus basalis of meynert (NBM) increases extracellular levels of glial D-serine Combined stimulation of mouse whiskers and the NBM, the principal source of cholinergic innervation to the cortex, leads to enhanced whisker-evoked local field potential. This plasticity is dependent on muscarinic acetylcholine receptors (mAChR) and N-methyl-d-aspartic acid receptors (NMDARs).
  50. 50. EphB3 and EphA4 receptors expressed in the adult hippocampus are involved in the regulation of D-serine levels and synaptic transmission. Hruska & Dalva (2012) Nol Cell Neurosci
  51. 51. Zhuang et al. (2010) J. Neurosci EphB3 and EphA4 receptors expressed in the adult hippocampus are involved in the regulation of D-serine levels and synaptic transmission.
  52. 52. Take home messages Martineau et al. (2014) Front Synaptic Neurosci
  53. 53. Take home messages The identitiy of the co-agonist for NMDARs is synapse specific  The identity of the co-agonist is developmentally regulated and parrallels the developmental switch from GluN2B to GluN2A subunits The synaptic identity of the co-agonist is profiled by proper astrocyte-neuron coupling Era 1 = Glycine era (1987 - 2000) Era 3 = Glycine/D-serine era (>2012) Era 2 = D-serine era (2000 - 2012)
  54. 54. Thank you! Gliotransmission and synaptopathies team CRN2M UMR7286 CNRS Université Aix-Marseille 13344 Marseille Cedex 15 – France jean-pierre.mothet@univ-amu.fr
  55. 55. Shigetomi et al. (2013) J. Neurosci Extracellular levels of D-serine are regulated by TRPA1 channel function

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