Ketamine's rapid and sustained antidepressant effects are driven by distinct mechanisms

Cell Mol Life Sci. 2024 Feb 27;81(1):105. doi: 10.1007/s00018-024-05121-6.ABSTRACTAdministration of multiple subanesthetic doses of ketamine increases the duration of antidepressant effects relative to a single ketamine dose, but the mechanisms mediating this sustained effect are unclear. Here, we demonstrate that ketamine's rapid and sustained effects on affective behavior are mediated by separate and temporally distinct mechanisms. The rapid effects of a single dose of ketamine result from increased activity of immature neurons in the hippocampal dentate gyrus without an increase in neurogenesis. Treatment with six doses of ketamine over two weeks doubled the duration of behavioral effects after the final ketamine injection. However, unlike ketamine's rapid effects, this more sustained behavioral effect did not correlate with increased immature neuron activity but instead correlated with increased numbers of calretinin-positive and doublecortin-positive immature neurons. This increase in neurogenesis was associated with a decrease in bone morphogenetic protein (BMP) signaling, a known inhibitor of neurogenesis. Injection of a BMP4-expressing lentivirus into the dentate gyrus maintained BMP signaling in the niche and blocked the sustained - but not the rapid - behavioral effects of ketamine, indicating that decreased BMP signaling is necessary for ketamine's sustained effects. Thus, although the rapid effects of ketamine result from increased activity of immature neurons in ...

Source: Cellular and Molecular Life Sciences : CMLS - February 27, 2024 Category: Cytology Authors: Radhika Rawat Elif Tunc-Ozcan Sara Dunlop Yung-Hsu Tsai Fangze Li Ryan Bertossi Chian-Yu Peng John A Kessler Source Type: research