Ketamine strengthens synaptic inputs to the dorsal raphé to boost serotonergic activity: pivotal for rapid antidepressant-like effects
Soukaina Es-Safi, Céline Bourcier-Lucas, Erika Abrial, Adeline Cathala, Thierry Lesté-Lasserre, Philippe De Deurwaerdère, Jean-Michel Revest, Jean Mazella, Nasser Haddjeri, Guillaume Lucas
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study (electrophysiology, microdialysis, and molecular assays in rats) |
|---|---|
| Population | Male Sprague-Dawley rats |
| Interventions | Ketamine Torin-2 |
| Dose | 10 mg/kg, i.p. |
| Duration | Recordings over 4-5 hours after injection; assessments up to 48 hours post-injection |
| Measures | 5-HT neuron mean firing rate (electrophysiology), microdialysis measurements of 5-HT release, PSD-95 and Synapsin-1 mRNA and protein levels, dentate gyrus cell proliferation (mitogenesis) |
| Topics | Esketamine Ketamine Serotonin |
| Key findings | Low-dose ketamine produced a delayed (2-5 hour) roughly 90% increase in dorsal raphé serotonin neuron firing and parallel hippocampal serotonin release, dependent on the medial prefrontal cortex and mTOR, while plasticity markers rose at 2-24 hours and dentate gyrus cell proliferation increased at 48 hours in a serotonin-dependent manner. The authors argue serotonin acts as an integrative hub transferring ketamine-induced neuroplastic changes across the brain. |
Abstract
ABSTRACT 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 raphé 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. SIGNIFICANCE STATEMENT This study helps reconcile two theories, often opposed to explain antidepressant (AD) action: the “serotonergic hypothesis” proposing that AD efficacy primarily results from an increase of serotonin, and the “neuroplastic theory” whereby only significant changes in brain connectivity can explain mood improvement. Here we show that ketamine, a drug exerting AD effects much faster than classical molecules do, augments synaptic strength onto serotonergic neurons, which subsequently triggers an elevation of serotonin. In turn, this enhanced serotonergic neurotransmission leads to the production of new neurons in the hippocampus, therefore reshaping the circuitry of this brain area. The serotonergic system appears to transfer the neuroplastic changes induced by ketamine across the brain, thus behaving like an integrative hub for its AD action.