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.

Translating the Habenula—From Rodents to Humans

“…Pharmacological inhibition of LHb by the GABA agonist muscimol had antidepressant effects in congenital helpless rats (33), and opposite metabolic alterations in Hb (high) and VTA (low) were observed in these rats (34). A very recent study also showed that enhancement of GABA-GIRK function in the LHb ameliorates depressive-like behaviors in mice (35). …”

G Protein-Gated Potassium Channels: A Link to Drug Addiction

“…Recently, an aversive stimulus, i.e., inescapable foot shock, was shown to decrease GABA B R-GIRK currents in LHb neurons [95]. Though the stimulus was different, the plasticity in GABA B R-GIRK currents may depend on the same PP2A-mediated GABA B2 S783 dephosphorylation mechanism described in VTA GABA neurons with psychostimulants [90, 95]. To confirm this, additional experiments are needed to determine whether there is a change in phosphorylation of GABA B2 S783.…”

“…To confirm this, additional experiments are needed to determine whether there is a change in phosphorylation of GABA B2 S783. Significantly, systemic administration of a PP2A inhibitor, LB-100, ameliorated the depressive-like behavioral effects of inescapable foot shock [95]. …”

“…Because the effect of reward/aversion is mediated over different time courses and in different neurons within the reward circuitry, we expect the outcome to have divergent effects on behavior. The ability of systemic LB-100 treatment to reverse depressive behaviors mediated by downregulation of GABA B R-GIRK currents [95] points to a promising avenue for the treatment of addiction.…”

mGluR-LTD at Excitatory and Inhibitory Synapses in the Lateral Habenula Tunes Neuronal Output

“…Moreover, in rodent models of addiction and depression, glutamatergic and GABAergic synaptic plasticity modulates LHb neuronal firing, which is in turn instrumental for depression-like phenotypes (Lecca et al., 2016, Maroteaux and Mameli, 2012, Meye et al., 2015, Shabel et al., 2014). This highlights the behavioral relevance of synaptic adaptations in the LHb, heightening the need of understanding its underlying cellular processes.…”