CB1 cannabinoid receptors and on-demand defense against excitotoxicity.
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.
Marsicano
Giovanni
G
Molecular Genetics of Behaviour, Max-Planck-Institute of Psychiatry, Kraepelinstrabetae 2-10, 80804 Munich, Germany.
Goodenough
Sharon
S
Monory
Krisztina
K
Hermann
Heike
H
Eder
Matthias
M
Cannich
Astrid
A
Azad
Shahnaz C
SC
Cascio
Maria Grazia
MG
Gutiérrez
Silvia Ortega
SO
van der Stelt
Mario
M
López-Rodriguez
Maria Luz
ML
Casanova
Emilio
E
Schütz
Günther
G
Zieglgänsberger
Walter
W
Di Marzo
Vincenzo
V
Behl
Christian
C
Lutz
Beat
B
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002186:Cannabinoids / Q000378:metabolism*; D063388:Endocannabinoids; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D005663:Furans / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D017781:Genes, Immediate-Early; D018698:Glutamic Acid / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000077285:Rimonabant; D015398:Signal Transduction; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001095:Arachidonic Acids; D019208:Brain-Derived Neurotrophic Factor; D002186:Cannabinoids; D063388:Endocannabinoids; D018690:Excitatory Amino Acid Agonists; D005663:Furans; D005989:Glycerides; C443680:N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide; D018696:Neuroprotective Agents; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C094503:glyceryl 2-arachidonate; D020928:Mitogen-Activated Protein Kinases; D000077285:Rimonabant; D007608:Kainic Acid; C078814:anandamide