Ketamine, the NMDAR antagonist, has revolutionized depression treatment because of its robust, rapid and sustained antidepressant effects. Recently, it was discovered that ketamine inhibits the NMDAR-dependent burst firing of the brain’s anti-reward center, the lateral habenula (LHb). By silencing the LHb bursts, ketamine can potentially disinhibit the aminergic reward circuits downstream of the LHb to exert its rapid antidepressant effects.
However, at least three key questions have remained unaddressed. Firstly, does blockade of LHb burst firing contribute to ketamine’s sustained antidepressant effects? Secondly, given that NMDARs are ubiquitously expressed, which specific brain region is the primary target of ketamine? Thirdly, will a drug targeting the same cellular/circuit mechanism of ketamine have similar antidepressant effects? In this talk, I will present our ongoing efforts in addressing these three urgent questions, which will hopefully illuminate a more unified theory on ketamine’s mode of action and inspire new treatment strategies for depression.