Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice

Nat Med. 2016 Mar;22(3):254-61. doi: 10.1038/nm.4037. Epub 2016 Jan 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • Bridged Bicyclo Compounds, Heterocyclic
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • LB100
  • Piperazines
  • Receptors, GABA-B
  • Protein Phosphatase 2