TY  - JOUR
PY  - 2016//
TI  - Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice
JO  - Nature medicine
A1  - Lecca, Salvatore
A1  - Pelosi, Assunta
A1  - Tchenio, Anna
A1  - Moutkine, Imane
A1  - Lujan, Rafael
A1  - Hervé, Denis
A1  - Mameli, Manuel
SP  - 254
EP  - 261
VL  - 22
IS  - 3
N2  - 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.<p />  <p>Language: en</p>
LA  - en
SN  - 1078-8956
UR  - http://dx.doi.org/10.1038/nm.4037
ID  - ref1
ER  -