Ketamine strengthens synaptic inputs to the dorsal raphe to boost serotonergic activity: pivotal for rapid antidepressant-like effects

Ketamine at subanaesthetic dose is known as a fast-acting antidepressant (AD), able to facilitate synaptic plasticity in the medial prefrontal cortex (mPFC) or the hippocampus. However, its influence on the serotonergic (5-HT) system is more confusing as it loses its behavioral effects in 5-HT-depleted animals, but does not modify 5-HT neuron function. We hypothesized that this discrepancy was due to the different temporal scales chosen in the related studies. We performed electrophysiological recordings of 5-HT neurons in the dorsal raphe nucleus (DRN) and microdialysis measurements of 5-HT release in the ventral hippocampus of male Sprague-Dawley rats. Experiments were designed to collect the results over a long duration, i.e. 4-5 hours after the injection. Levels of the pro-neuroplastic factors PSD-95 and Synapsin-1 in the DRN were also assessed, as was cell proliferation in the dentate gyrus (DG). 5-HT neuron mean firing rate was unmodified within the 2 h that followed ketamine (10 mg/kg, i.p.), but strongly (90%) increased in the 2-5 h time bin, an effect abolished by lesioning the mPFC or administering the mTOR inhibitor Torin-2. A similar kinetics was found for hippocampal 5-HT release. Synapsin-1 and PSD-95 mRNA transcriptions were enhanced at 2 h, and PSD-95 protein levels appeared to peak at 24 h. Finally, DG mitogenesis was enhanced 48 h post-injection, an augmentation suppressed in 5-HT-depleted animals. Low-dose ketamine provokes a neuroplastic wave originating in the mPFC and emerging in the hippocampus, a transfer in which the 5-HT system appears to act as an integrative hub of plasticity.