1 / 54

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists. Nanxin Li, et al. Science 329 , 959 (2010) R1 黃泰翰 V.S. 洪成志 2010.09.21. Ketamine. Antagonist of Glutamate NMDA receptor analgesia, anesthesia, sedation

tayte
Download Presentation

mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Nanxin Li, et al. Science 329, 959 (2010) R1 黃泰翰V.S. 洪成志2010.09.21

  2. Ketamine • Antagonist of Glutamate NMDA receptor • analgesia, anesthesia, sedation • Psychological effects similar to phencyclidine (PCP) • Dissociative state • Hallucination • Schizophrenia like symptoms

  3. Behavior model of depression • Despair • Forced Swim Test (FST) • Learned hopelessness(LH) • Anxiety • Novelty-Suppressed Feeding Test (NSFT)

  4. Forced Swim Test (FST) • 1st swim for 15 mins - 24 hrs later • drug treatment - 24hrs later • 2nd swim for 5 mins • Duration of Immobility

  5. Learned-Helplessness (LH) • Inescapable footshock (IES) • 60 footshocks, • duration: 15 s, • intershock interval: 60 s • -24hrs- drug treatment -24hrs- • Active avoidance testing • 30 trials of escapable footshock • duration: 35s • Number of escape failure recorded

  6. Novelty-Suppressed Feeding Test (NSFT) • food-deprived for 24hrs • placed in an open field • 76.5 cm X 76.5 cm X 40 cm • food in the center • latency to feed

  7. Placebo controlled, double-blinded trial 18 subjects with treatment refractory MDD A single low dose of Ketamine (0.5mg/Kg) A Randomized Trial of an NMDA Antagonist in Treatment-Resistant Major Depression C. A. Zarate Jr. et al., Arch. Gen. Psychiatry 63, 856 (2006).

  8. Ketamine Signaling Pathway? Anti-depression effects

  9. mTOR Signaling Pathway • Mammalian target of rapamycin • Rapamycin = Sirolimus • Immunosuppresant • Ubiquitous • Protein kinase • translation regulation • S6K • 4E-BP

  10. Translation Regulation • Protein Synthesis • Translation from mRNA • Initiation, elongation, termination • Regulation • eIF (eukaryotic initiation factor) • eEF • Ribosome

  11. S6K • S6K phosphorylates ribosomal protein S6, • component of the small, 40S ribosomal subunit. • 4E-BP • eIF4E binding protein

  12. Methods • Ketamine • intraperitoneal injection • Measurement • Synaptoneurosome in Prefrontal Cortex

  13. Ketamine (ip) induce transient, dose-dependent mTOR signaling in synaptoneurosome of PFC 10 mg/Kg 1 hr

  14. ECS Electroconvulsive seizure, imipramine, or fluoxetine did not significantly influence mTOR signaling Chronic (21D) Acute (1hr)

  15. Ketamine 4E-BP mTOR S6K

  16. mTOR and growth factor signaling pathway • MAPK/ERK cascade • Extracellular signal–regulated kinase • Mitogen-activated protein kinase • MAP3K -> MAP2K -> MAPK • Akt/PKB pathway • PI3K -> PDK -> Akt C. A. Hoeffer, E. Klann, Trends Neurosci.33, 67 (2010)

  17. Ketamine transiently and dose-dependently increases pERK & pAkt 1 hr 10 mg/Kg

  18. Pretreatment (30 mins before Ketamine):U0126 (20 nmol, ICV): inhibitors of ERKLY294002 (20 nmol, ICV): inhibitor of PI-3k/Akt

  19. 4E-BP mTOR S6K Ketamine ERK, Akt

  20. Glutamate receptor • Ionotropic Glutamate receptor • NMDA receptor • AMPA receptor • Kainate receptor • Metabotropic Glutamate receptor

  21. Antidepressant actions of ketamine & AMPA receptor • Glutamate AMPA receptor • NBQX • a selective AMPA receptor inhibitor • it attenuate the reduction in immobility time induced by ketamine • Pretreatment (10 min before Ketamine) with NBQX (10 mg/kg, ip) S. Maeng et al., Biol. Psychiatry63, 349 (2008).

  22. NBQX blocked ketamine activation of mTOR signaling and upstream ERK & Akt

  23. 4E-BP mTOR S6K Ketamine AMPA ERK, Akt

  24. mTOR and synaptic protein synthesis • Presynaptic protein: • Synapsin I • Postsynaptic proteins: • PSD95, GluR1 • Arc: • activity-regulated cytoskeletal-associated protein C. A. Hoeffer, E. Klann, Trends Neurosci.33, 67 (2010).

  25. Ketamine induces intermediate (1-2 hr) but transient increase of Arc • Ketamine induces delayed (2-72 hr) increase of synaptic proteins • Pretreatment (30 min) with a selective mTOR inhibitor, rapamycin (0.2 nmol, ICV) block the effect

  26. Synape Formation ?

  27. Dendritic spine formation Y. Yoshihara, M. De Roo, D. Muller, Curr. Opin. Neurobiol. 19, 146 (2009).

  28. Spine density analysis • Layer V Pyramidal Cell in PFC • Tips of tuft branches approaching the pial membrane • Proximal tuft dendrites just distal to the bifurcation • Density • Head diameter • Length

  29. ketamine increased spine density in distal and proximal segments of the apical tuft

  30. Head diameter Spine length

  31. Excitatory postsynaptic current (EPSC) • Apical dendrites of Layer V pyramidal cells in mPFC • 5-HT and Hypocretin Increase EPSCs • Restraint stress • 5-HT and hypocretin-induced EPSCs decreased • Apical tuft dendritic branch length and spine density decreased R. J. Liu, G. K. Aghajanian, Proc. Natl. Acad. Sci. U.S.A.105, 359 (2008).

  32. EPSC measurement

  33. Rapamycin was infused (0.2 nmol, ICV) 30 min before ketamine (10 mg/kg, ip) • Rapid behavioral actions of ketamine require mTOR signaling

  34. Infusion of rapamycin (0.01 nmol) into the mPFCblocked the antidepressant actions of ketamine (10 mg/kg, ip) in the FST and NSFT

  35. Pretreatment with inhibitors of • ERK (U0126, 20 nmol, ICV) or • PI3 kinase / Akt (LY294002, 20 nmol, ICV) • block of ketamine effects in FST and NSFT

  36. Learned helpless with Inescapable Shock (IES) • Synapsin I, PSD95 and GluR1 • Ketamine given 24hr after IES • Tissue collected 24 hr after ketamine • Single dose of ketamine reverse this effect • Pretreatment with rapamycin (ICV, 30 min before) block ketamine effect

  37. Dose-dependent ketamine antidepressant action • FST • Low dose • 10 mg/kg • high anesthetic dose • 80 mg/kg • Similar with dose of ERK, Akt, and mTOR induction

  38. Ketamine for Depression ? • Risk of abuse and adverse effects • Ro 25-6981 • selective NMDA receptor subunit 2B (NR2B) antagonists • NMDA Receptor = 2 NR1 + 2 NR2 • NR1: 8 subtype • NR2: 4 subtype • NR2A, NR2B, NR2C, NR2D

  39. Ro 25-6981 produced rapid (24 hr before), dose-dependent antidepressant action in the FST

  40. Pretreatment with rapamycin (0.2 nmol, ICV) abolished the actions of Ro 25-6981 (10 mg/kg, ip) in FST and NSFT

More Related