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Revised Model of Endocannabinoid Signaling

Revised Model of Endocannabinoid Signaling. Cannabinoids Medically and traditionally used for thousands of years Active compound of marijuana ( D 9 -THC) identified in 1964 Brain cannabinoid receptor (CB1) identified in 1990.

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Revised Model of Endocannabinoid Signaling

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  1. Revised Model of Endocannabinoid Signaling

  2. Cannabinoids • Medically and traditionally used for thousands of years • Active compound of marijuana (D9-THC) identified in 1964 • Brain cannabinoid receptor (CB1) identified in 1990. • CB1 is one of the most abundant G-protein coupled receptors in the brain • Another receptor (CB2) is absent in brain, but enriched in immune tissues • Most (but not all) effects of D9-THC are absent in CB1-/- mice • “CBX” receptor may exist

  3. Cannabinoids At central synapses (hippocampus, cerebellum, neocortex), cannabinoids are released in an activity dependent way, and inhibit presynaptic neurotransmitter release (Depolarization induced Supression of Inhibition/Excitation)

  4. Depolarization induced suppression of inhibition (DSI)

  5. The First Problem

  6. Cannabinoids Endocannabinoids Synthetic cannabinoids

  7. Direct modulation of ligand-gated ion channels: Acetylcholine receptor, Serotonin 5HT3 receptor (frog oocyte experiments)

  8. Direct modulation of ligand-gated ion channels: Acetylcholine receptor, Serotonin 5HT3 receptor (frog oocyte experiments)

  9. Research questions Do cannabinoids modulate GABAergic synaptic transmission by a direct action on ionotropic GABAA receptors? If yes, what does this modulation mean for local neuronal circuits

  10. CB1R agonists modulate currents through recombinant GABAAR

  11. CB1R agonists modulate currents through recombinant GABAAR

  12. Cannabinoids show CB1 receptor independent reduction of GABAA mediated response

  13. Experimental Procedure Paired recordings from a FS interneuron innervating a pyramidal neuron

  14. Cannabinoids show CB1 receptor independent reduction of GABAA mediated response

  15. Cannabinoids show CB1 receptor independent reduction of GABAA mediated response

  16. Postsynaptic depolarization causes a CB1R-independent suppression of inhibitory synaptic transmission.

  17. Endocannabinoid synthesis and degradation Diacylglycerol Lipase (DAGL) Monoacylglycerol Lipase (MAGL) Cyclooxygenase-2 (COX-2) Fatty acid amide hydrolase (FAAH)

  18. Anandamide synthesis and degradation

  19. Postsynaptic depolarization causes a CB1R-independent suppression of inhibitory synaptic transmission. RHC80267 & THL: Diacylglycerol Lipase inhibitors URB602 Monoacylglycerol Lipase inhibitor Nimesulide: Cyclooxygenase-2 inhibitor

  20. Modulation of microcircuit coupling by cannabinoids

  21. The effect of CP on hippocampal CCK-positive interneuron to CA1 pyramidal neuron connections in wild-type, CB1R-/- and GABAAR a2-/-mice.

  22. Potentiation of extrasynaptic GABAARs by endocannabinoids

  23. Dual effect of cannabinoids on GABAARs

  24. Conclusions These results indicate that: Cannabinoids in addition to the presynaptic (retrograde) mode of action, can suppress inhibition by a direct modulation of postsynaptic GABAA receptors. 2. Suppression of inhibition by a direct modulation of postsynaptic GABAA receptors has a high impact on a neuronal network activity providing a new dimension in cannabinoid signaling.

  25. Golovko Tatiana Heidelberg University • Falconer Caroline Dundee University • Min Rogier • Lozovaya Natalia VrijeUniversiteit Amsterdam • Burnashev Nail Institut de Neurobiologie de la Méditerranée

  26. Depolarization induced suppression of inhibition (DSI) R I Wilson, R A Nicoll Science 2002;296:678-682

  27. Chronic Suppression of Inhibition (CSI) WT Control AM 251 CB1 KO

  28. Chronic suppression of inhibition (CSI) ? • Pre- or postsynaptic origin? • Suitable candidate(s) for mediating the effect ? • Presynaptic calcium regulation?

  29. CCK (CB1R +) interneurons Location Firing pattern CCK 20 mV 200 ms PYR CCK Asynchronous release Recording protocol PYR CCK

  30. Blocking CB1Rs relieves CSI SR/AM

  31. IPSCs potentiated in WT but not CB1 KO mice

  32. Blocking 2-AG synthesis has no effect on CSI THL 2AG THL

  33. Chelation of presynaptic calcium potentiates IPSCs AM251 CCK CCK CCK PYR PYR PYR

  34. A presynaptic calcium-dependent process suppresses IPSCs EGTA AM EGTA AM

  35. Half maximal IPSC potentiation with 0.1 mM BAPTA

  36. Brief extracellular BAPTA applicationpotentiates IPSCs 10 mM BAPTA CCK PYR

  37. CSI time course + AEA/2-AG/CP

  38. AEA a potential candidate mediating CSI

  39. Presynaptic calcium regulation: frequency dependence CB1R CCK PYR GABAbR 7 s 12 s 30 s 7 s

  40. What : CSIWhere : PresynapticWho : Anandamide Why:

  41. Perisomatic inhibition Freund T and Katona, Neuron 2007; 56:33-42

  42. Synaptic inputs Freund T, TINS 2003; 489-495

  43. . When: In vivo firing patterns

  44. Bolshakov Alex • Falconer Caroline • Carl Holmgren Dundee University

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