The ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] exhibits rapid antidepressant effects without the psychotomimetic or addictive side effects associated with ketamine, making it a promising therapeutic candidate. However, the precise molecular targets and mechanisms underlying its antidepressant actions remain controversial. In this study, we identified TREK-1, a two-pore domain potassium channel, as a key target of (2R,6R)-HNK. Electrophysiological experiments revealed that (2R,6R)-HNK selectively inhibits TREK-1 currents, with an ICclose to its effective antidepressant concentration. TREK-1 is widely expressed in the brain, and its activity in the mPFC has been implicated in regulating depressive-like behaviors. Early-life stress increases TREK-1 expression in the mPFC, impairing synaptic plasticity and neural circuit formation, which contributes to emotional disorders. Further investigations demonstrated that (2R,6R)-HNK enhances the firing frequency of mPFC pyramidal neurons and upregulates synaptic plasticity-related proteins, including CREB and PSD95. Crucially, the antidepressant effects of (2R,6R)-HNK were abolished in mice with pyramidal neuron-specific knockdown of TREK-1 in the mPFC, confirming the essential role of TREK-1 inhibition in mediating (2R,6R)-HNK's actions. Our findings establish TREK-1 as a critical target for (2R,6R)-HNK's rapid antidepressant effects, providing new insights into the mechanisms of depression treatment and the development of novel therapeutics. 50
