title: Analysis in conditional cannabinoid 1 receptor-knockout mice reveals neuronal subpopulation-specific effects on epileptogenesis in the kindling paradigm.
abstract: The endocannabinoid system serves as a retrograde negative feedback mechanism. It is thought to control neuronal activity in an epileptic neuronal network. The purpose of this study was to evaluate the impact of the endocannabinoid and endovanilloid systems on both epileptogenesis and ictogenesis. Therefore, we modulated the endocannabinoid and endovanilloid systems genetically and pharmacologically, and analyzed the subsequent impact on seizure progression in the kindling model of temporal lobe epilepsy in mice. In addition, the impact of seizures on associated cellular alterations was evaluated. Our principal results revealed that the endocannabinoid system affects seizure and afterdischarge duration dependent on the neuronal subpopulation being modulated. Genetic deletion of CB1-receptors (CB1Rs) from principal neurons of the forebrain and pharmacological antagonism with rimonabant (5 mg/kg) caused longer seizure duration. Deletion of CB1R from GABAergic forebrain neurons resulted in the opposite effect. Along with these findings, the CB1R density was elevated in animals with repetitively induced seizures. However, neither genetic nor pharmacological interventions had any impact on the development of generalized seizures. Other than CB1, genetic deletion or pharmacological blockade with SB366791 (1 mg/kg) of transient receptor potential vanilloid receptor 1 (TRPV1) had no effect on the duration of behavioral or electrographic seizure activity in the kindling model. In conclusion, we demonstrate that endocannabinoid, but not endovanilloid, signaling affects termination of seizure activity, without influencing seizure severity over time. These effects are dependent on the neuronal subpopulation. Thus, the data argue that the endocannabinoid system plays an active role in seizure termination but does not regulate epileptogenesis.
authors.affiliation: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians University, Munich, Germany; Graduate School of Systemic Neurosciences, Munich, Germany.
authors.forename: E L
authors.initials: EL
authors.lastname: von Rüden
authors.affiliation: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians University, Munich, Germany; Graduate School of Systemic Neurosciences, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Jafari
authors.affiliation: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians University, Munich, Germany; Graduate School of Systemic Neurosciences, Munich, Germany.
authors.forename: R M
authors.initials: RM
authors.lastname: Bogdanovic
authors.affiliation: Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: C T
authors.initials: CT
authors.lastname: Wotjak
authors.affiliation: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians University, Munich, Germany. Electronic address: potschka@pharmtox.vetmed.uni-muenchen.de.
authors.forename: H
authors.initials: H
authors.lastname: Potschka
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001973:Bromodeoxyuridine; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists / Q000009:adverse effects; D002934:Cinnamates / Q000494:pharmacology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007696:Kindling, Neurologic / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines / Q000009:adverse effects; D016548:Prosencephalon / Q000473:pathology*; D011720:Pyrazoles / Q000009:adverse effects; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency*; D000077285:Rimonabant; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000813:Anilides; D063387:Cannabinoid Receptor Antagonists; D002934:Cinnamates; C543264:Cnr1 protein, rat; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D005680:gamma-Aminobutyric Acid; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; C517598:Camk1 protein, mouse; D001973:Bromodeoxyuridine; D000077285:Rimonabant
keywords: Amygdala; CB1; Endovanilloid; GABA; Glutamate; Hyperexcitable network; Ictogenesis; Neurogenesis; Seizure; TRPV1