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.

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Figure 1: FsE induces cellular adaptations in the LHb and a depression-like phenotype.
Figure 2: Subcellular plasticity of GABABRs and GIRKs in the LHb.
Figure 3: PP2A inhibition rescues GABAB-GIRK function in the LHb after FsE.
Figure 4: GABABR-dependent control of activity in the LHb after FsE.
Figure 5: PP2A inhibition in vivo rescues GABAB-GIRK function and hyperexcitability in the LHb.
Figure 6: PP2A inhibition ameliorates core symptoms of depression.

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Acknowledgements

We thank C. Bellone, M. Carta, E. Schwartz, C. Lüscher, F.J. Meye and members of the Mameli laboratory for discussions and comments on the manuscript. This work was supported by funds from the INSERM Atip-Avenir program (M.M.), a European Research Council starting grant (grant no. SalienSy 335333; M.M.), the Paris School of Neuroscience Network (ENP) Chair of Excellence (M.M.) and the Junta de Comunidades de Castilla–La Mancha (grant no. PPII-2014-005-P; R.L.). The Mameli laboratory is part of the Initiative of Excellence Labex BioPsy network. We thank J. Kovach and Lixte Biotechnology Holdings, Inc. for the gift of LB-100. The monoclonal antibody specific to GABAB1 (clone N93A/49) was developed by the University of California, Davis–US National Institutes of Health NeuroMab facility (Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis).

Author information

S.L. and M.M. performed and analyzed all of the in vitro electrophysiological recordings and behavioral experiments with the help of A.T.; A.P. and D.H. designed and performed biochemical assays; I.M. performed immunohistochemistry and designed the viral vector; R.L. performed electron microscopy and analyzed the data; and S.L. and M.M. wrote the manuscript.

Correspondence to Manuel Mameli.

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Lecca, S., Pelosi, A., Tchenio, A. et al. Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice. Nat Med 22, 254–261 (2016). https://doi.org/10.1038/nm.4037

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