Presynaptic NMDA receptors on mouse mossy fiber terminals mediate rapid BDNF release by ketamine and hydroxynorketamine.

Enhancement of neuronal plasticity is a key determinant of the onset of antidepressant responses. Because brain-derived neurotrophic factor (BDNF)-dependent synaptic plasticity is essential for antidepressant efficacy, we examined whether fast-acting antidepressants directly trigger BDNF release. At antidepressant-relevant concentrations, ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) induced BDNF secretion from mossy fiber terminals of granule neurons within minutes of application in rat hippocampal cultures. BDNF release required selective NMDAR signaling, as conditional genetic deletion of presynaptic NMDARs from granule neurons or from postsynaptic NMDARs from CA3 pyramidal neurons in acute mouse hippocampal slices, abolished BDNF exocytosis in response to both ketamine and HNK or selectively to HNK, respectively. Both compounds produced acute synaptic plasticity, reflected by gains and losses of CA3 dendritic spines without a net change in overall spine density. These findings reveal distinct, drug-specific NMDAR mechanisms at mossy fiber terminal-CA3 synapses that drive rapid BDNF release by fast-acting antidepressants.