title: Cannabinoid agonists rearrange synaptic vesicles at excitatory synapses and depress motoneuron activity in vivo.
abstract: Impairment of motor skills is one of the most common acute adverse effects of cannabis. Related studies have focused mainly on psychomotor alterations, and little is known about the direct impact of cannabinoids (CBs) on motoneuron physiology. As key modulators of synaptic function, CBs regulate multiple neuronal functions and behaviors. Presynaptic CB1 mediates synaptic strength depression by inhibiting neurotransmitter release, via a poorly understood mechanism. The present study examined the effect of CB agonists on excitatory synaptic inputs incoming to hypoglossal motoneurons (HMNs) in vitro and in vivo. The endocannabinoid anandamide (AEA) and the synthetic CB agonist WIN 55,212-2 rapidly and reversibly induced short-term depression (STD) of glutamatergic synapses on motoneurons by a presynaptic mechanism. Presynaptic effects were fully reversed by the CB1-selective antagonist AM281. Electrophysiological and electron microscopy analysis showed that WIN 55,212-2 reduced the number of synaptic vesicles (SVs) docked to active zones in excitatory boutons. Given that AM281 fully abolished depolarization-induced depression of excitation, motoneurons can be feasible sources of CBs, which in turn act as retrograde messengers regulating synaptic function. Finally, microiontophoretic application of the CB agonist O-2545 reversibly depressed, presumably via CB1, glutamatergic inspiratory-related activity of HMNs in vivo. Therefore, evidence support that CBs, via presynaptic CB1, induce excitatory STD by reducing the readily releasable pool of SVs at excitatory synapses, then attenuating motoneuron activity. These outcomes contribute a possible mechanistic basis for cannabis-associated motor performance disturbances such as ataxia, dysarthria and dyscoordination.
authors.affiliation: Grupo de Neurodegeneración y Neuroreparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: García-Morales
authors.affiliation: Grupo de Neurodegeneración y Neuroreparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Montero
authors.affiliation: Grupo de Neurodegeneración y Neuroreparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain. Electronic address: bernardo.moreno@uca.es.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Moreno-López
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001578:Benzopyrans / Q000494:pharmacology; D001933:Brain Stem / Q000166:cytology* / Q000648:ultrastructure; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007478:Iontophoresis; D008297:Male; D046529:Microscopy, Electron, Transmission; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects* / Q000648:ultrastructure; D013572:Synaptic Vesicles / Q000187:drug effects*
chemical_list: D001578:Benzopyrans; D063386:Cannabinoid Receptor Agonists; D018683:Excitatory Amino Acid Agents; D007093:Imidazoles; C000603032:O-2545
keywords: AMPAergic neurotransmission; CB1 receptors; Depolarization-induced suppression of excitation; Hypoglossal motoneurons; Short-term depression