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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.

Pubmed ID: 14526074

Authors

  • Marsicano G
  • Goodenough S
  • Monory K
  • Hermann H
  • Eder M
  • Cannich A
  • Azad SC
  • Cascio MG
  • Gutiérrez SO
  • van der Stelt M
  • López-Rodriguez ML
  • Casanova E
  • Schütz G
  • Zieglgänsberger W
  • Di Marzo V
  • Behl C
  • Lutz B

Journal

Science (New York, N.Y.)

Publication Data

October 3, 2003

Associated Grants

None

Mesh Terms

  • Animals
  • Arachidonic Acids
  • Brain
  • Brain-Derived Neurotrophic Factor
  • Cannabinoids
  • Endocannabinoids
  • Epilepsy
  • Excitatory Amino Acid Agonists
  • Excitatory Postsynaptic Potentials
  • Furans
  • Gene Expression Regulation
  • Genes, Immediate-Early
  • Glutamic Acid
  • Glycerides
  • Hippocampus
  • In Vitro Techniques
  • Kainic Acid
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases
  • Mutation
  • Neurons
  • Neuroprotective Agents
  • Piperidines
  • Polyunsaturated Alkamides
  • Prosencephalon
  • Pyrazoles
  • Receptors, Cannabinoid
  • Receptors, Drug
  • Signal Transduction
  • gamma-Aminobutyric Acid