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 GABA(B) receptor (GABA(B)R) and G protein gated inwardly rectifying potassium (GIRK) channel surface expression. Accordingly, FsE triggers GABA(B1) and GIRK2 internalization, leading to rapid and persistent weakening of GABA(B)-activated GIRK-mediated (GABA(B)-GIRK) currents. Pharmacological inhibition of PP2A restores both GABA(B)-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, GABA(B)-GIRK-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.