Original Article

Molecular Psychiatry (2017) 22, 920–930; doi:10.1038/mp.2016.188; published online 8 November 2016

Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state

T Fuchs1,6, S J Jefferson1,6, A Hooper2, P-HP Yee1, J Maguire3 and B Luscher1,4,5

  1. 1Department of Biology, Pennsylvania State University, University Park, PA, USA
  2. 2Graduate Program in Neuroscience, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA
  3. 3Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA
  4. 4Department of Biochemistry & Molecular Biology, Pennsylvania State University, University Park, PA, USA
  5. 5Center for Molecular Investigation of Neurological Disorders (CMIND), Pennsylvania State University, University Park, PA, USA

Correspondence: Professor B Luscher, Department of Biology, Pennsylania State University, 301 Life Sciences Building, University Park, PA 16802, USA. E-mail: BXL25@psu.edu

6These authors contributed equally to this work.

Received 4 May 2016; Revised 14 August 2016; Accepted 31 August 2016
Advance online publication 8 November 2016



Major 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 acting antidepressants.