Article: article from journal or magazin.
Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice.
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.
Animals, Behavior, Animal/drug effects, Bridged Bicyclo Compounds, Heterocyclic/pharmacology, Depression/metabolism, Disease Models, Animal, Electroshock, G Protein-Coupled Inwardly-Rectifying Potassium Channels/drug effects, G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics, G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism, Habenula/drug effects, Habenula/metabolism, Helplessness, Learned, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Microscopy, Electron, Motor Activity, Neuronal Plasticity/drug effects, Patch-Clamp Techniques, Phenotype, Piperazines/pharmacology, Protein Phosphatase 2/antagonists & inhibitors, Receptors, GABA-B/drug effects, Receptors, GABA-B/metabolism, Restraint, Physical, Reverse Transcriptase Polymerase Chain Reaction, Stress, Psychological/metabolism
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