Abstract
Ketamine, a well-known anesthetic, has recently attracted renewed attention as a fast-acting antidepressant. A single dose of ketamine induces rapid synaptogenesis, which may underlie its antidepressant effect. To test whether repeated exposure to ketamine triggers sustained synaptogenesis, we administered a sub-anesthetic dose of ketamine (10 mg/kg i.p.) once-daily for 5 days, and repeatedly imaged dendritic spines of the YFP-expressing pyramidal neurons in somatosensory cortex of awake female mice using in vivo two-photon microscopy. We found that the spine formation rate became significantly higher at 72–132 h after the first ketamine injection (but not at 6–24 h), while the rate of elimination of pre-existing spines remained unchanged. In contrast to the net gain of spines observed in ketamine-treated mice, the vehicle-injected control mice exhibited a net loss typical for young-adult animals undergoing synapse pruning. Ketamine-induced spinogenesis was correlated with increased PSD-95 and phosphorylated actin, consistent with formation of new synapses. Moreover, structural synaptic plasticity caused by ketamine was paralleled by a significant improvement in the nest building behavioral assay. Taken together, our data show that subchronic low-dose ketamine induces a sustained shift towards spine formation.
Highlights
Ketamine, a well-known anesthetic, has recently attracted renewed attention as a fast-acting antidepressant
Longitudinal in vivo two-photon microscopy was employed to show the stimulating effects of a single i.p. injection of ketamine on dendritic spine formation and density in medial frontal cortex of isoflurane-anesthetized mice[11]
We investigated in awake behaving mice whether subchronic administration of low-dose ketamine induces long-lasting changes in the dendritic spine turnover in somatosensory cortex
Summary
A well-known anesthetic, has recently attracted renewed attention as a fast-acting antidepressant. A single dose of ketamine induces rapid synaptogenesis, which may underlie its antidepressant effect. Consumption of ketamine induces vivid sensations with hallucinations leading to a dissociative state, manifest as a sensation of detachment (dissociation) from the environment and from one’s own body. Duman and coauthors have shown that a single intraperitoneal (i.p.) administration of ketamine in mice at the dose of 10 mg/kg rapidly increases synaptic protein levels and dendritic spine number in prefrontal cortex through activation of the mTOR signaling pathway[8]. Longitudinal in vivo two-photon microscopy was employed to show the stimulating effects of a single i.p. injection of ketamine on dendritic spine formation and density in medial frontal cortex of isoflurane-anesthetized mice[11]
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