The role of endocannabinoid-mediated signaling in normal and pathological operations os hippocampal circuits  Page description

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Details of project

  
Identifier
46820
Type K
Principal investigator Freund, Tamás
Title in Hungarian Az endocannabinoid-mediált szignalizáció funkciója a hippocampus neuronhálózatainak normális és kóros működéseiben
Title in English The role of endocannabinoid-mediated signaling in normal and pathological operations os hippocampal circuits
Panel Neurosciences
Department or equivalent Laboratory of Cerebral Cortex Research (Institute of Experimental Medicine)
Participants Borhegyi, Zsolt
Gulyás, Attila
Hájos, Norbert
Katona, István
Maglóczky, Zsófia
Makara, Judit
Mátyás, Ferenc
Nyíri, Gábor Péter
Szabó, Gábor
Varga, Viktor
Starting date 2004-01-01
Closing date 2007-12-31
Funding (in million HUF) 24.149
FTE (full time equivalent) 0.00
state closed project





 

Final report

  
Results in Hungarian
Az OTKA pályázat támogatásával az elmúlt négy évben alapvető felismeréseket tettünk egy új kémiai szignálrendszer, az endokannabinoid rendszer molekuláris és anatómiai szerveződéséről, élettani és kórélettani jelentőségéről. Kimutattuk, hogy az endokannabinoid rendszer egy specializált jelátviteli rendszer, amelynek feladata, hogy a szinapszisok működését a preszinaptikus és a posztszinaptikus idegsejt aktivitásának függvényében szabályozza. Elsőként írtuk le egy endokannabinoid molekula, a 2-arachidonilglicerol kulcsszerepét ebben a folyamatban, és feltártuk, hogy milyen molekuláris mechanizmusok szabályozzák keletkezését és lebontását. Igazoltuk, hogy ez a kémiai szignálrendszer számos agyterületen (agykéregben, hippocampusban, nucleus accumbensben, a ventrális tegmentális areában) megtalálható. Élettani kísérleteink alapján az endokannabinoidok egy negatív visszacsatolási folyamat közvetítői a szinapszisokban. Ezzel párhuzamosan felfedeztük, hogy az endokannabinoid rendszer működési zavarai kulcsszerepet játszhatnak a temporális lebeny eredetű epilepsziában, valamint a szorongásos és poszttraumatikus stressz-okozta panaszok hátterében is megtalálhatók. Ezek az eredményeink egyben új molekuláris gyógyszercélpontokat jelölnek ki, amelyek számos idegrendszeri megbetegedésben vezethetnek hatékonyabb és szelektívebb farmakoterápia kidolgozásához.
Results in English
During the last four years, our research group has reached fundamental milestones in the understanding of a new chemical messenger system, the so-called endocannabinoid system. We have uncovered the molecular and anatomical organization of endocannabinoid signaling and provided clues for its physiological and pathophysiological importance. We have shown that the endocannabinoid system is a specialized signaling machinery, which controls the efficacy synaptic transmission as a function of the activity of presynaptic and postsynaptic neurons. We have described for the first time that 2-arachidonoylglycerol is a key player in this process, and uncovered the basic mechanisms in its biosynthesis and degradation. We have provided evidence that this chemical signaling mechanism is a conserved feature of several types of synapses in various brain regions, for example in the neocortex, hippocampus, nucleus accumbens and the ventral tegmental area. We have shown that this system is involved in a negative feed-back regulation of transmitter release, and described its impairment in the human epileptic hippocampus, as well as its contribution to anxiety and post-traumatic stress disorder in animal models. These findings unravel new drug targets, whereby they could open novel therapeutic approaches for a more efficient and selective treatment of several brain disorders.
Full text http://real.mtak.hu/1590/
Decision
Yes





 

List of publications

  
Nyiri G., Cserép Cs., Szabadits E., Mackie K. and Freund TF: CB1 cannabinoid receptors are enriched in the perisynaptic annulus and on preterminal segments of hippocampal GABAergic axons, Neuroscience 136: 811-822, 2005
Nyíri G., Cserép Cs., Szabadits E., Ken Mackie K. and Freund TF: GABAB and CB1 cannabinoid receptor expression identifies two types of septal cholinergic neurons, European Journal of Neuroscience 21: 3034-3042, 2005
Haller J, Szirmai M, Varga B, Ledent C, Freund TF: Cannabinoid CB1 receptor dependent effects of the NMDA antagonist phencyclidine in the social withdrawal model of schizophrenia, Behav Pharmacol 16: 415-422, 2005
Bodor AL, Katona I, Nyíri G, MacKie K, Ledent C, Hájos N, Freund TF: Endocannabinoid signaling in rat somatosensory cortex: laminar differences and involvement of specific interneuron types, J Neurosci 25: 6845-6856, 2005
Matyas F, Yanovsky Y, Mackie K, Kelsch W, Misgeld U, Freund TF.: Subcellular localization of type 1 cannabinoid receptors in the rat basal ganglia., Neuroscience 137: 337-361, 2006
Gulyás AI, Buzsáki G, Freund TF, Hirase H: Populations of hippocampal inhibitory neurons express different levels of cytochrome c, Eur J Neurosci 23: 2581-2594, 2006
Mikics E, Dombi T, Barsvari B, Varga B, Ledent C, Freund TF, Haller J: The effects of cannabinoids on contextual conditioned fear in CB1 knockout and CD1 mice, Behav Pharmacol 17: 223-230, 2006
Haller J, Mátyás F, Soproni K, Varga B, Barsy B, Németh B, Mikics É, Freund TF, Hájos N: Correlated species differences in the effects of cannabinoid ligands on anxiety and on GABAergic and glutamatergic synaptic transmission, Eur J Neurosci 25: 2445-2456, 2007
Mátyás F, Watanabe M, Mackie K, Katona I, Freund TF: Molecular architecture of the cannabinoid signaling system in the core of the nucleus accumbens, Ideggyógyászati Szemle 60: 187-191, 2007
Eyre MD, Freund TF, Gulyás AI: quantitative ultrastructural differences between local and medial septal gabaergic axon terminals in the rat hippocampus, Neuroscience 149: 537-548, 2007
Benninger F, Freund TF, Hajos N: Control of excitatory synaptic transmission by capsaicin is unaltered in TRPV(1) vanilloid receptor knockout mice, Neuroscem Int 52: (1-2) 89-94, 2008
Mátyás F, Urbán GM, Watanabe M, Mackie K, Zimmer A, Freund TF, Katona I: Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both gabaergic and glutamatergic synapses in the ventral tegmental area, Neuropharmacology 54: 95-107, 2008
Nemeth B, Ledent C, Freund TF, Hajos N: CB(1) receptor-dependent and -independent inhibition of excitatory postsynaptic currents in the hippocampus by win 55,212-2, Neuropharmacology 54: (1) 51-57, 2008
Hajos N, Palhalmi J, Mann EO, Nemeth B, Paulsen O, Freund TF.: Spike timing of distinct types of GABAergic interneuron during hippocampal gamma oscillations in vitro., Journal of Neuroscience, 24: 9127-9137., 2004
Bernard C, Milh M, Morozov YM, Ben Ari Y, Freund TF, Gozlan H: Altering cannabinoid signaling during development disrupts neuronal activity, Proc Natl Acad Sci USA 102: 9388-9393, 2005
Maglóczky Zs, Freund TF: Impaired and repaired inhibitory circuits in the epileptic human hippocampus, Trends Neurosci 28: 334-340, 2005
Makara JK, Mor M, Fegley D, Szabó SI, Kathuria S, Astarita G, Duranti A, Tontini A, Tarzia G, Rivara S, Freund TF, Piomelli D: Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus, Nat Neurosci 8: 1139-1141, 2005
Katona I, Urbán GM, Wallace M, Ledent C, Jung KM, Piomelli D, Mackie K, Freund TF: Molecular composition of the endocannabinoid system at glutamatergic synapses, J Neurosci 26: 5628-5637, 2006
Freund TF, Katona I: Perisomatic inhibition, Neuron 56: (1) 33-42, 2007
Makara JK, Katona I, Nyiri G, Nemeth B, Ledent C, Watanabe M, de Vente J, Freund TF, Hajos N: Involvement of nitric oxide in depolarization-induced suppression of inhibition in hippocampal pyramidal cells during activation of cholinergic receptors, J Neurosci 27: (38) 10211-10222, 2007
Szabadits E, Cserep C, Ludanyi A, Katona I, Gracia Llanes J, Freund TF, Nyiri G: Hippocampal gabaergic synapses possess the molecular machinery for retrograde nitric oxide signaling, J Neurosci 27: (30) 8101-8111, 2007
Ludányi A, Erőss L, Czirják S, Vajda P, Halász P, Watanabe M, Palkovits M, Maglóczky Z, Freund TF, Katona I: Down-regulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus, J Neurosci in press, 2008
Nyilas R, Dudok B, Urbán GM, Mackie K, Watanabe M, Cravatt BF, Freund TF, Katona I: Enzymatic machinery for endocannabinoid biosynthesis associated with calcium stores in glutamatergic axon terminals, J Neurosci 28: (5) 1058-1063, 2008



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