title: Endocannabinoids produced upon action potential firing evoke a Cl(-) current via type-2 cannabinoid receptors in the medial prefrontal cortex.
abstract: The functional presence of type-2 cannabinoid receptors (CB2Rs) in layer II/III pyramidal neurons of the rat medial prefrontal cortex (mPFC) was recently demonstrated. In the present study, we show that the application of the endocannabinoids (eCBs) 2-arachidonoylglycerol (2-AG) and methanandamide [a stable analog of the eCB anandamide (AEA)] can activate CB2Rs of mPFC layer II/III pyramidal neurons, which subsequently induces a Cl(-) current. In addition, we show that action potential (AP) firing evoked by 20-Hz current injections results in an eCB-mediated opening of Cl(-) channels via CB2R activation. This AP-evoked synthesis of eCBs is dependent on the Ca(2+) influx through N-type voltage-gated calcium channels. Our results indicate that 2-AG is the main eCB involved in this process. Finally, we demonstrate that under physiologically relevant intracellular Cl(-) conditions, 20-Hz AP firing leads to a CB2R-dependent reduction in neuronal excitability. Altogether, our data indicate that eCBs released upon action potential firing can modulate, through CB2R activation, neuronal activity in the mPFC. We discuss how this may be a mechanism to prevent excessive neuronal firing.
authors.affiliation: Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH, Amsterdam, The Netherlands.
authors.forename: Femke S
authors.initials: FS
authors.lastname: den Boon
authors.forename: Pascal
authors.initials: P
authors.lastname: Chameau
authors.forename: Kas
authors.initials: K
authors.lastname: Houthuijs
authors.forename: Simone
authors.initials: S
authors.lastname: Bolijn
authors.forename: Nicolina
authors.initials: N
authors.lastname: Mastrangelo
authors.forename: Chris G
authors.initials: CG
authors.lastname: Kruse
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Wytse J
authors.initials: WJ
authors.lastname: Wadman
authors.forename: Taco R
authors.initials: TR
authors.lastname: Werkman
mesh_terms: D000200:Action Potentials; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D063388:Endocannabinoids / Q000494:pharmacology*; D005989:Glycerides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D020864:Calcium Channels, N-Type; D002712:Chlorides; D063388:Endocannabinoids; D005989:Glycerides; D043885:Receptor, Cannabinoid, CB2; C088155:methanandamide; C094503:glyceryl 2-arachidonate