A metabolite of ketamine, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], produces rapid and sustained antidepressant effects in animal models without the side effects of ketamine and without blocking the NMDA receptor. The antidepressant effects require activity-dependent release of BDNF, mediated by stimulation of voltage-dependent Ca2+ channels. Increased BDNF release activates downstream TrkB and mechanistic target of rapamycin complex 1 signaling, which increases synaptic function of pyramidal neurons in the medial prefrontal cortex. Stimulation of BDNF release and increased synaptic function block or reverse the detrimental effects of stress and depression.
Chronic unpredictable stress in male rodents reduces GABAergic proteins and the frequency of inhibitory postsynaptic currents in layer V pyramidal neurons of the medial prefrontal cortex, accompanied by depression-like behaviors. A single dose of ketamine reverses these stress-induced deficits in GABA markers and depressive-like behaviors. The findings indicate that impairments of GABAergic synapses are key determinants of depressive behavior and that ketamine restores both GABA inhibitory and glutamate neurotransmission.
A single dose of NV-5138, a small molecule that modulates sestrin and crosses the blood-brain barrier, produced rapid and long-lasting antidepressant effects and quickly reversed anhedonia caused by chronic stress in mice. These effects required BDNF release in the medial prefrontal cortex, as blocking BDNF with an antibody or using a BDNF polymorphism that prevents activity-dependent release eliminated the behavioral responses. NV-5138 also rapidly increased synapse number and function in the medial prefrontal cortex and reversed synaptic deficits from chronic stress. The findings indicate that pharmacologically modulating sestrin activates mTORC1 signaling and BDNF release, offering a new approach for rapid-acting antidepressants.
Ketamine, an NMDA receptor antagonist, rapidly relieves symptoms of depression within hours. While neuroplasticity in the medial prefrontal cortex (mPFC) is known to be critical for these effects, the downstream brain circuits involved were unclear. Using optogenetic and chemogenetic techniques in rodent models, researchers identified two distinct pathways. Activation of mPFC projections to the basolateral amygdala (BLA) and then to the ventral hippocampus mediated ketamine's effects on passive coping behavior, but not on anxiety or reward-seeking. In contrast, mPFC projections to the bed nucleus of stria terminalis (BNST) were necessary and sufficient for effects on anxiety-like and reward-seeking behaviors, but not passive coping. This suggests separate downstream circuits produce different antidepressant-like behavioral responses.