Year: 2026
Type: article
Abstract: Ketamine (KET) produces rapid and long-lasting antidepressant effects at subanesthetic doses. However, the underlying mechanisms by which KET regulates the function of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons, a key brain area involved in the regulation of emotional behaviors, including depression, remains largely unknown. Here, we show that KET increases the firing activity of DRN 5-HT neurons while bidirectionally modulating their excitatory inputs in cell-type-specific manner. Retrograde circuit mapping reveals that KET preferentially potentiates glutamatergic synapses of DRN 5-HT neurons projecting to medial prefrontal cortex, while depressing glutamate synapses of those projecting to central amygdala (CeA). Notably, KET-induced synaptic potentiation in the DRN—but not the increase in 5-HT neuronal firing—was abolished by blockade of the brain-derived neurotrophic factor (BDNF) receptor TrkB. These findings indicate the presence of parallel TrkB-dependent and TrkB-independent signaling pathways that regulate DRN 5-HT neuron function. Collectively, our results uncover previously unsuspected mechanisms by which KET modulates central serotonergic transmission and provide new mechanistic insight into its antidepressant effects.
Source: iScience
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,240
OpenAlex ID: W7167815215