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Science 3 October 2003:
Vol. 302. no. 5642, pp. 84 - 88
DOI: 10.1126/science.1088208
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Research Articles

CB1 Cannabinoid Receptors and On-Demand Defense Against Excitotoxicity

Giovanni Marsicano,1* Sharon Goodenough,2,4* Krisztina Monory,1* Heike Hermann,1 Matthias Eder,3 Astrid Cannich,1 Shahnaz C. Azad,3,5 Maria Grazia Cascio,6 Silvia Ortega Gutiérrez,7 Mario van der Stelt,6 Maria Luz López-Rodríguez,7 Emilio Casanova,8 Günther Schütz,8 Walter Zieglgänsberger,3 Vincenzo Di Marzo,6 Christian Behl,2,4{dagger} Beat Lutz1{dagger}{ddagger}

Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant mice that lack expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory interneurons. In mutant mice,the excitotoxin kainic acid (KA) induced excessive seizures in vivo. The threshold to KA-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. KA administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wild-type principal hippocampal neurons. These protective mechanisms could not be triggered in mutant mice. The endogenous cannabinoid system thus provides on-demand protection against acute excitotoxicity in central nervous system neurons.

1 Molecular Genetics of Behaviour, Max-Planck-Institute of Psychiatry, Kraepelinstraße 2-10, 80804 Munich, Germany.
2 Neurodegeneration, Max-Planck-Institute of Psychiatry, Kraepelinstraße 2-10, 80804 Munich, Germany.
3 Clinical Neuropharmacology Group, Max-Planck-Institute of Psychiatry, Kraepelinstraße 2-10, 80804 Munich, Germany.
4 Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg–University, Duesbergweg 6, 55099 Mainz, Germany.
5 Clinic of Anaesthesiology, LudwigMaximilians-University, Klinikum Grosshadern, Marchioninistraße 15, 81377 Munich, Germany.
6 Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy.
7 Department of Organic Chemistry, Complutense University, 28040 Madrid, Spain.
8 Division of Molecular Biology of the Cell I, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.



* These authors contributed equally to this work.

{dagger} These authors share senior authorship.

{ddagger} To whom correspondence should be addressed. E-mail: lutz{at}mpipsykl.mpg.de

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