Temporal dynamics of BDNF signaling recruitment in the rat prefrontal cortex and hippocampus following a single infusion of a translational dose of ketamine

Despite several decades of investigations, the mechanisms underlying the rapid action of ketamine as antidepressant are still far from being completely understood. Several studies indicated Brain-Derived Neurotrophic Factor (BDNF) as critical for the fast antidepressant action of ketamine, due to its contribution in early and rapid synaptic adaptations. However, previous reports have been essentially based on ketamine dosing modes that differ from the clinical route of administration (slow intravenous infusion). In this report, we investigated the effects of a ketamine dosing mode in male Sprague-Dawley rats showed to be translational to the clinically effective mode in patients. We focused on the first 24 h after infusion to finely dissect potential differences in the contribution of BDNF signaling pathway in prefrontal cortex and hippocampus, two brain regions involved in the antidepressant effects of ketamine. Our data show that the slow ketamine infusion activates the BDNF-mTOR-S6 pathway in prefrontal cortex as early as 2 h and remains on until at least 6 h after the infusion. At the 12 h timepoint, this pathway is turned off in prefrontal cortex while it becomes activated in hippocampus. Interestingly, this pathway appears to be activated in both brain regions at 24 h through a BDNF-independent mechanism adding complexity to the early action of ketamine. We have captured previously unknown dynamics of the early effects of ketamine showing rapid activation/deactivation of BDNF and its downstream signaling in prefrontal cortex and hippocampus, following a precise temporal profile.