“As elimination of TREK1 induces an antidepressant-like phenotype, novel TREK1 blockers could have antidepressant effects.”

Serotonergic neurotransmission is involved in both the pathophysiology of depression and the effects of antidepressants such as selective serotonin reuptake inhibitors (SSRIs), but the underlying molecular mechanisms are poorly understood. Writing in Nature Neuroscience, Lazdunski and colleagues show that knockout of the potassium channel TREK1, which is regulated by serotonin and also inhibited by some SSRIs, has antidepressant effects, and so could be a potential target for novel antidepressants.

Several lines of evidence point to a role for TREK1 in serotonin function. TREK1 is a two-pore domain potassium ion channel and a member of a distinct class of ion channels involved in setting the resting potential and regulating the overall excitability of individual neurons. The TREK1 ion channel is regulated by G-coupled receptors including several types of serotonin receptor, is homologous with other ion channels controlled by serotonin and is expressed in areas of the brain believed to mediate cognitive aspects of depression.

To explore the function of TREK1, the authors studied TREK1-deficient mice in a battery of behavioural models that have been shown to be useful in predicting the antidepressant activity of drugs. In all the models, mice lacking TREK1 were more resistant to developing symptoms linked to depression than were wild-type mice. Moreover, the behaviour of TREK1-deficient mice closely resembled that of wild-type mice that had been treated with SSRIs.

Electrophysiological tests of serotonin-responsive neurons in the brain showed that, compared with wild-type neurons, the neurons of TREK1-deficient mice had an increased level of activation, as if they had been chronically treated with an antidepressant. Consistent with the involvement of serotonin, depletion of the neurotransmitter using a combination of agents to block its synthesis, reuptake and recycling reversed the depression-resistant phenotype of TREK1-deficient mice.

Mice lacking the related potassium ion channel TRAAK did not show an antidepressant phenotype in animal models, displayed normal serotonin transmission and remained sensitive to treatment with antidepressants, suggesting that the effects observed following TREK1 deletion are not a general property of this class of ion channel.

As elimination of TREK1 induces an antidepressant-like phenotype, novel TREK1 blockers could have antidepressant effects. Indeed, fluoxetine and other SSRIs partially inhibit TREK1 at brain concentrations that are comparable with those achieved following clinical dosing in humans, suggesting that the action of these drugs might be mediated in part through TREK1. The role of TREK1 in processes such as neuroprotection raises concerns about potential side effects, but it might offer an opportunity to develop drugs that are efficacious in the considerable proportion of patients who are unresponsive to current therapies.