Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Ward 10-233, Chicago, IL, 60611, USA. radhika.rawat@northwestern.edu.
2 papers in the library · 86 citations · publishing 2022-2024
Activation of adult-born immature granule neurons (ABINs) in the mouse hippocampal dentate gyrus is both necessary and sufficient for the rapid antidepressant effects of ketamine. Ketamine activates ABINs in stressed and unstressed mice. Chemogenetic inhibition of ABIN activity blocks ketamine's antidepressant effects, while chemogenetic activation of ABINs mimics both the cellular and behavioral effects of ketamine without changing neuron numbers. These findings identify ABINs as a specific cell population mediating ketamine's antidepressant actions, suggesting that targeting ABINs could preserve therapeutic efficacy while limiting side effects.
Ketamine's rapid and sustained antidepressant effects rely on separate biological mechanisms. A single dose rapidly improves mood by increasing activity of immature neurons in the hippocampal dentate gyrus without generating new neurons. Six doses over two weeks doubled the duration of behavioral improvement, which correlated with increased numbers of immature neurons (neurogenesis) and reduced bone morphogenetic protein (BMP) signaling, a known inhibitor of neurogenesis. Experimentally maintaining BMP signaling with a lentivirus blocked the sustained but not the rapid effects, showing that decreased BMP signaling and increased neurogenesis are necessary for ketamine's long-lasting benefits. Understanding these dual mechanisms may aid development of safer, sustained antidepressant therapies.