title: Presynaptic calcium channel inhibition underlies CB₁ cannabinoid receptor-mediated suppression of GABA release.
abstract: CB1 cannabinoid receptors (CB1) are located at axon terminals and effectively control synaptic communication and thereby circuit operation widespread in the CNS. Although it is partially uncovered how CB1 activation leads to the reduction of synaptic excitation, the mechanisms of the decrease of GABA release upon activation of these cannabinoid receptors remain elusive. To determine the mechanisms underlying the suppression of synaptic transmission by CB1 at GABAergic synapses, we recorded unitary IPSCs (uIPSCs) at cholecystokinin-expressing interneuron-pyramidal cell connections and imaged presynaptic [Ca(2+)] transients in mouse hippocampal slices. Our results reveal a power function with an exponent of 2.2 between the amplitude of uIPSCs and intrabouton [Ca(2+)]. Altering CB1 function by either increasing endocannabinoid production or removing its tonic activity allowed us to demonstrate that CB1 controls GABA release by inhibiting Ca(2+) entry into presynaptic axon terminals via N-type (Cav2.2) Ca(2+) channels. These results provide evidence for modulation of intrabouton Ca(2+) influx into GABAergic axon terminals by CB1, leading to the effective suppression of synaptic inhibition.
authors.affiliation: Lendület Laboratory of Network Neurophysiology, and.
authors.forename: Gergely G
authors.initials: GG
authors.lastname: Szabó
authors.affiliation: Lendület Laboratory of Cellular Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, Hungary.
authors.forename: Nora
authors.initials: N
authors.lastname: Lenkey
authors.affiliation: Lendület Laboratory of Cellular Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, Hungary.
authors.forename: Noemi
authors.initials: N
authors.lastname: Holderith
authors.affiliation: Lendület Laboratory of Network Neurophysiology, and.
authors.forename: Tibor
authors.initials: T
authors.lastname: Andrási
authors.affiliation: Lendület Laboratory of Cellular Neurophysiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1450 Budapest, Hungary hajos@koki.hu nusser@koki.hu.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Nusser
authors.affiliation: Lendület Laboratory of Network Neurophysiology, and hajos@koki.hu nusser@koki.hu.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hájos
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002766:Cholecystokinin / Q000235:genetics / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010880:Piperidines / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D008164:Luminescent Proteins; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C413663:fluorescent protein 583; C103505:AM 251; D005680:gamma-Aminobutyric Acid; D002766:Cholecystokinin; D020866:omega-Conotoxin GVIA; D002118:Calcium
keywords: GABAergic interneuron; endocannabinoid; hippocampus; mouse