Disinhibition of somatostatin-positive GABAergic interneurons results in
an anxiolytic and antidepressant-like brain state.
Fuchs T1, Jefferson SJ1, Hooper A2, Yee PH1, Maguire J3, Luscher B1,4,5.
depressive disorder (MDD) is associated with reduced concentrations of
γ-aminobutyric acid (GABA) that are normalized by antidepressant therapies.
Moreover, depressive-like phenotypes of GABAA receptor
mutant mice can be reversed by treatment with conventional antidepressants
drugs, as well as by subanesthetic doses of ketamine. Thus GABAergic deficits may causally contribute to
depressive disorders, while antidepressant therapies may enhance GABAergic synaptic transmission. Here we tested
the hypothesis that sustained enhancement of GABAergic transmission
alone is sufficient to elicit antidepressant-like behavior,
using disinhibition of GABAergic interneurons.
We focused on somatostatin-positive (SST+) GABAergic interneurons because
of evidence that their function is compromised in MDD. To disinhibit SST+ interneurons, we inactivated the γ2 subunit gene of GABAA receptors
selectively in these neurons (SSTCre:γ2f/f mice).
Loss of inhibitory synaptic input resulted in increased excitability of SST+interneurons. In turn, pyramidal cell targets
of SST+ neurons showed an increased frequency of spontaneous
inhibitory postsynaptic currents. The behavior of SSTCre:γ2f/f mice
mimicked the effects of anxiolytic and
antidepressant drugs in a number of behavioral tests, without affecting
performance in a spatial learning- and memory-dependent task. Finally, brain extracts of SSTCre:γ2f/f mice
showed decreased phosphorylation of the eukaryotic elongation factor eEF2,
reminiscent of the effects of ketamine. Importantly, these effects occurred
without altered activity of the mammalian target of rapamycin pathway nor did
they involve altered expression of SST. However, they were associated with
reduced Ca2+/calmodulin-dependent auto-phosphorylation of
eEF2 kinase, which controls the activity of eEF2 as its single target. Thus
enhancing GABAergic inhibitory synaptic
inputs from SST+ interneurons to pyramidal
cells and corresponding chronic reductions in the synaptic
excitation:inhibition ratio represents a novel strategy for antidepressant
therapies that reproduces behavioral and biochemical end points of rapidly