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

Abstract

Major Depressive Disorder 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. Lastly, brain extracts of SSTCre:γ2f/f mice showed decreased phosphorylation of the eukaryotic elongation factor eEF2, reminiscent of effects of ketamine. Importantly, these effects occurred without altered activity of the mTOR 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 endpoints of rapidly acting antidepressants.

Mechanisms of ketamine action as an antidepressant

“…In particular, ketamine administration to mice with a global reduction of GABA A receptor function, reversed behavioral despair and novelty-induced hyper-anxiety and selectively potentiated GABAergic synaptic inhibition within the mPFC 53 . Similarly, potentiation of GABAergic inhibitory input to pyramidal cells via a disinhibition of somatostatin-positive GABAergic interneurons induced sustained antidepressant-like effects in mice 54 . Enhancement of inhibition with pharmacological activation of GABA A or GABA B receptors also resulted in an antidepressant effect in rats 55, 56 .…”

Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives

“…Increasing SST interneuron inhibitory input onto target neurons (through genetic deletion of the γ2-subunit gene restricted to SST cells) demonstrated antidepressant- and anxiolytic-like activity in mice (112). Directly enhancing post-synaptic targets of SST interneurons may represent an alternative strategy.…”

“…through synaptogenesis or potentiation of α5-GABA A receptor (α5-GABA A R) function (135, 136)). (3) Similarly, transgenic (Tg) mice heterozygous for SST interneuron γ2-GABA A R-subunit knockout demonstrate an antidepressant- and anxiolytic-like behavioral profile, putatively resulting from disinhibition of SST interneuron function (112). Experimental compounds that promote SST cell integrity, e.g., by increasing brain-derived neurotrophic factor (BDNF)-TrKB signaling (4) or inhibiting protein kinase RNA-like endoplasmic reticulum (PERK) and therefore endoplasmic reticulum (ER) stress (5) , have shown antidepressant-like action in rodent stress models (85, 149).…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…In particular, GABAergic synaptic cortical disinhibition induced via a global reduction of GABA A receptor function, increased baseline behavioral despair in the forced-swim test and latency for food consumption in the novelty-suppressed feeding test in mice [169–171], indicative of a depressive-related phenotype. In addition, disinhibition of somatostatin-positive GABAergic interneuron activity in mice, resulting in an enhanced interneuron excitability, and thus inhibition of pyramidal neuron activity induced antidepressant-related behavioral responses in mice (i.e., reduced latency to feed in the novelty-suppressed feeding test and decreased escape failures in the learned helplessness paradigm) [172]; however long-term deletion of GABA A receptors could result in compensatory changes that might contribute to the observed behavioral effects.…”