title: Pro-brain-derived neurotrophic factor inhibits GABAergic neurotransmission by activating endocytosis and repression of GABAA receptors.
abstract: GABA is the canonical inhibitory neurotransmitter in the CNS. This inhibitory action is largely mediated by GABA type A receptors (GABAARs). Among the many factors controlling GABAergic transmission, brain-derived neurotrophic factor (BDNF) appears to play a major role in regulating synaptic inhibition. Recent findings have demonstrated that BDNF can be released as a precursor (proBDNF). Although the role of mature BDNF on GABAergic synaptogenesis and maintenance has been well studied, an important question still unanswered is whether secreted proBDNF might affect GABAergic neurotransmission. Here, we have used 14 d in vitro primary culture of hippocampal neurons and ex vivo preparations from rats to study the function of proBDNF in regulation of GABAAR trafficking and activity. We demonstrate that proBDNF impairs GABAergic transmission by the activation of two distinct pathways: (1) a RhoA-Rock-PTEN pathway that decreases the phosphorylation levels of GABAAR, thus affecting receptor function and triggering endocytosis and degradation of internalized receptors, and (2) a JAK-STAT-ICER pathway leading to the repression of GABAARs synthesis. These effects lead to the diminution of GABAergic synapses and are correlated with a decrease in GABAergic synaptic currents. These results revealed new functions for proBDNF-p75 neurotrophin receptor signaling pathway in the control of the efficacy of GABAergic synaptic activity by regulating the trafficking and synthesis of GABAARs at inhibitory synapses.
authors.affiliation: Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale Unité 901, and Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, 13273 Marseille, France.
authors.forename: Baptiste
authors.initials: B
authors.lastname: Riffault
authors.affiliation: Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale Unité 901, and Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, 13273 Marseille, France.
authors.forename: Igor
authors.initials: I
authors.lastname: Medina
authors.affiliation: Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale Unité 901, and Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, 13273 Marseille, France.
authors.forename: Camille
authors.identifier: http://orcid.org/0000-0002-1625-3091
authors.initials: C
authors.lastname: Dumon
authors.affiliation: Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale Unité 901, and Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, 13273 Marseille, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Thalman
authors.affiliation: Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale Unité 901, and Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, 13273 Marseille, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Ferrand
authors.affiliation: Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale Unité 901, and Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, 13273 Marseille, France.
authors.forename: Perrine
authors.initials: P
authors.lastname: Friedel
authors.affiliation: Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale Unité 901, and Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, 13273 Marseille, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Gaiarsa
authors.affiliation: Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale Unité 901, and Institut de Neurobiologie de la Méditerranée, Parc Scientifique de Luminy, 13273 Marseille, France Christophe.porcher@inserm.fr.
authors.forename: Christophe
authors.identifier: http://orcid.org/0000-0002-6026-6367
authors.initials: C
authors.lastname: Porcher
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D011810:Quinoxalines; D018079:Receptors, GABA; D026941:Sodium Channel Blockers; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine
keywords: BDNF; GABAA receptors; intracellular trafficking; synaptic plasticity