PMID- 25274828 OWN - NLM STAT- MEDLINE DCOM- 20150120 LR - 20211021 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 34 IP - 40 DP - 2014 Oct 1 TI - Pro-brain-derived neurotrophic factor inhibits GABAergic neurotransmission by activating endocytosis and repression of GABAA receptors. PG - 13516-34 LID - 10.1523/JNEUROSCI.2069-14.2014 [doi] AB - 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. CI - Copyright (c) 2014 the authors 0270-6474/14/3413516-19$15.00/0. FAU - Riffault, Baptiste AU - Riffault B AD - Aix-Marseille Universite, Institut National de la Sante et de la Recherche Medicale Unite 901, and Institut de Neurobiologie de la Mediterranee, Parc Scientifique de Luminy, 13273 Marseille, France. FAU - Medina, Igor AU - Medina I AD - Aix-Marseille Universite, Institut National de la Sante et de la Recherche Medicale Unite 901, and Institut de Neurobiologie de la Mediterranee, Parc Scientifique de Luminy, 13273 Marseille, France. FAU - Dumon, Camille AU - Dumon C AUID- ORCID: 0000-0002-1625-3091 AD - Aix-Marseille Universite, Institut National de la Sante et de la Recherche Medicale Unite 901, and Institut de Neurobiologie de la Mediterranee, Parc Scientifique de Luminy, 13273 Marseille, France. FAU - Thalman, Carine AU - Thalman C AD - Aix-Marseille Universite, Institut National de la Sante et de la Recherche Medicale Unite 901, and Institut de Neurobiologie de la Mediterranee, Parc Scientifique de Luminy, 13273 Marseille, France. FAU - Ferrand, Nadine AU - Ferrand N AD - Aix-Marseille Universite, Institut National de la Sante et de la Recherche Medicale Unite 901, and Institut de Neurobiologie de la Mediterranee, Parc Scientifique de Luminy, 13273 Marseille, France. FAU - Friedel, Perrine AU - Friedel P AD - Aix-Marseille Universite, Institut National de la Sante et de la Recherche Medicale Unite 901, and Institut de Neurobiologie de la Mediterranee, Parc Scientifique de Luminy, 13273 Marseille, France. FAU - Gaiarsa, Jean-Luc AU - Gaiarsa JL AD - Aix-Marseille Universite, Institut National de la Sante et de la Recherche Medicale Unite 901, and Institut de Neurobiologie de la Mediterranee, Parc Scientifique de Luminy, 13273 Marseille, France. FAU - Porcher, Christophe AU - Porcher C AUID- ORCID: 0000-0002-6026-6367 AD - Aix-Marseille Universite, Institut National de la Sante et de la Recherche Medicale Unite 901, and Institut de Neurobiologie de la Mediterranee, Parc Scientifique de Luminy, 13273 Marseille, France Christophe.porcher@inserm.fr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Enzyme Inhibitors) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (Nerve Tissue Proteins) RN - 0 (Quinoxalines) RN - 0 (Receptors, GABA) RN - 0 (Sodium Channel Blockers) RN - 118876-58-7 (2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline) RN - 4368-28-9 (Tetrodotoxin) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - 76326-31-3 (2-amino-5-phosphopentanoic acid) RN - HG18B9YRS7 (Valine) SB - IM MH - Animals MH - Animals, Newborn MH - Brain-Derived Neurotrophic Factor/metabolism/*pharmacology MH - Endocytosis/*drug effects/physiology MH - Enzyme Inhibitors/pharmacology MH - Excitatory Amino Acid Antagonists/pharmacology MH - Gene Expression Regulation/drug effects MH - Hippocampus/cytology MH - Inhibitory Postsynaptic Potentials/drug effects MH - Nerve Tissue Proteins/metabolism MH - Neuronal Plasticity/drug effects MH - Neurons/*drug effects MH - Quinoxalines/pharmacology MH - Rats MH - Rats, Wistar MH - Receptors, GABA/*metabolism MH - Sodium Channel Blockers/pharmacology MH - Synaptic Transmission/*drug effects/physiology MH - Tetrodotoxin/pharmacology MH - Valine/analogs & derivatives/pharmacology MH - gamma-Aminobutyric Acid/*metabolism PMC - PMC6608319 OTO - NOTNLM OT - BDNF OT - GABAA receptors OT - intracellular trafficking OT - synaptic plasticity EDAT- 2014/10/03 06:00 MHDA- 2015/01/21 06:00 PMCR- 2015/04/01 CRDT- 2014/10/03 06:00 PHST- 2014/10/03 06:00 [entrez] PHST- 2014/10/03 06:00 [pubmed] PHST- 2015/01/21 06:00 [medline] PHST- 2015/04/01 00:00 [pmc-release] AID - 34/40/13516 [pii] AID - 2069-14 [pii] AID - 10.1523/JNEUROSCI.2069-14.2014 [doi] PST - ppublish SO - J Neurosci. 2014 Oct 1;34(40):13516-34. doi: 10.1523/JNEUROSCI.2069-14.2014.