title: Membrane-derived phospholipids control synaptic neurotransmission and plasticity.
abstract: Synaptic communication is a dynamic process that is key to the regulation of neuronal excitability and information processing in the brain. To date, however, the molecular signals controlling synaptic dynamics have been poorly understood. Membrane-derived bioactive phospholipids are potential candidates to control short-term tuning of synaptic signaling, a plastic event essential for information processing at both the cellular and neuronal network levels in the brain. Here, we showed that phospholipids affect excitatory and inhibitory neurotransmission by different degrees, loci, and mechanisms of action. Signaling triggered by lysophosphatidic acid (LPA) evoked rapid and reversible depression of excitatory and inhibitory postsynaptic currents. At excitatory synapses, LPA-induced depression depended on LPA1/Gαi/o-protein/phospholipase C/myosin light chain kinase cascade at the presynaptic site. LPA increased myosin light chain phosphorylation, which is known to trigger actomyosin contraction, and reduced the number of synaptic vesicles docked to active zones in excitatory boutons. At inhibitory synapses, postsynaptic LPA signaling led to dephosphorylation, and internalization of the GABAAγ2 subunit through the LPA1/Gα12/13-protein/RhoA/Rho kinase/calcineurin pathway. However, LPA-induced depression of GABAergic transmission was correlated with an endocytosis-independent reduction of GABAA receptors, possibly by GABAAγ2 dephosphorylation and subsequent increased lateral diffusion. Furthermore, endogenous LPA signaling, mainly via LPA1, mediated activity-dependent inhibitory depression in a model of experimental synaptic plasticity. Finally, LPA signaling, most likely restraining the excitatory drive incoming to motoneurons, regulated performance of motor output commands, a basic brain processing task. We propose that lysophospholipids serve as potential local messengers that tune synaptic strength to precedent activity of the neuron.
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.
authors.forename: David
authors.initials: D
authors.lastname: González-Forero
authors.affiliation: Grupo de Neurodegeneración y Neuroreparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Rodríguez-Bey
authors.affiliation: Grupo de Neurodegeneración y Neuroreparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Gómez-Pérez
authors.affiliation: Grupo de Neurodegeneración y Neuroreparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain; Salus Infirmorum, Universidad de Cádiz, Cádiz, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Medialdea-Wandossell
authors.affiliation: Grupo de Neurodegeneración y Neuroreparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.
authors.forename: Germán
authors.initials: G
authors.lastname: Domínguez-Vías
authors.affiliation: Centro de Investigación Príncipe Felipe, CIBERNED, Universidad de Valencia, Valencia, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García-Verdugo
authors.affiliation: Grupo de Neurodegeneración y Neuroreparación (GRUNEDERE), Área de Fisiología, Facultad de Medicina, Universidad de Cádiz, Cádiz, Spain.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Moreno-López
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D005260:Female; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000502:physiology*; D009473:Neuronal Plasticity; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D011963:Receptors, GABA-A; D054460:rho-Associated Kinases; D019703:Calcineurin; D020742:rhoA GTP-Binding Protein; C032881:lysophosphatidic acid