title: Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice.
abstract: The lateral habenula (LHb) encodes aversive signals, and its aberrant activity contributes to depression-like symptoms. However, a limited understanding of the cellular mechanisms underlying LHb hyperactivity has precluded the development of pharmacological strategies to ameliorate depression-like phenotypes. Here we report that an aversive experience in mice, such as foot-shock exposure (FsE), induces LHb neuronal hyperactivity and depression-like symptoms. This occurs along with increased protein phosphatase 2A (PP2A) activity, a known regulator of GABAB receptor (GABABR) and G protein-gated inwardly rectifying potassium (GIRK) channel surface expression. Accordingly, FsE triggers GABAB1 and GIRK2 internalization, leading to rapid and persistent weakening of GABAB-activated GIRK-mediated (GABAB-GIRK) currents. Pharmacological inhibition of PP2A restores both GABAB-GIRK function and neuronal excitability. As a consequence, PP2A inhibition ameliorates depression-like symptoms after FsE and in a learned-helplessness model of depression. Thus, GABAB-GIRK plasticity in the LHb represents a cellular substrate for aversive experience. Furthermore, its reversal by PP2A inhibition may provide a novel therapeutic approach to alleviate symptoms of depression in disorders that are characterized by LHb hyperactivity.
authors.affiliation: Institut du Fer à Moulin, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) S839, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lecca
authors.affiliation: Institut du Fer à Moulin, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) S839, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Assunta
authors.initials: A
authors.lastname: Pelosi
authors.affiliation: Institut du Fer à Moulin, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) S839, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Tchenio
authors.affiliation: Institut du Fer à Moulin, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) S839, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Imane
authors.initials: I
authors.lastname: Moutkine
authors.affiliation: Instituto de Investigación en Discapacidades Neurológicas, Albacete, Spain.|Universidad Castilla-La Mancha, Facultad de Medicina, Departamento de Ciencias Médicas, Campus Biosanitario, Albacete, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Lujan
authors.affiliation: Institut du Fer à Moulin, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) S839, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Hervé
authors.affiliation: Institut du Fer à Moulin, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) S839, Paris, France.|Université Pierre et Marie Curie, Paris, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mameli
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D003863:Depression / Q000378:metabolism*; D004195:Disease Models, Animal; D004597:Electroshock; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D019262:Habenula / Q000187:drug effects* / Q000378:metabolism; D006380:Helplessness, Learned; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009043:Motor Activity; D009473:Neuronal Plasticity / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D018080:Receptors, GABA-B / Q000187:drug effects* / Q000378:metabolism; D012149:Restraint, Physical; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C000708580:LB100; D010879:Piperazines; D018080:Receptors, GABA-B; D054648:Protein Phosphatase 2