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Mechanisms Mediating the Rapid and Sustained Antidepressant Effects of Ketamine.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Mechanisms Mediating the Rapid and Sustained Antidepressant Effects of Ketamine./
Author:	Rawat, Radhika.
Description:	1 online resource (182 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 84-11, Section: A.
Contained By:	Dissertations Abstracts International84-11A.
Subject:	Neurosciences. -
Online resource:	click for full text (PQDT)
ISBN:	9798379588588

Mechanisms Mediating the Rapid and Sustained Antidepressant Effects of Ketamine.
Rawat, Radhika.

Mechanisms Mediating the Rapid and Sustained Antidepressant Effects of Ketamine. - 1 online resource (182 pages)

Source: Dissertations Abstracts International, Volume: 84-11, Section: A.

Thesis (Ph.D.)--Northwestern University, 2023.

Includes bibliographical references

Major Depressive Disorder (MDD) is one of the top three causes of disability worldwide, but only 60-70% of patients with MDD respond to first-line therapies, and responders still have lasting impairments and recurrences. Thus, further research into the molecular basis of depression and antidepressant action is needed. Using chemogenetic techniques, our lab has previously established a causal relationship between changes in adult hippocampal neurogenesis and anxiety/depression-like behavior in mice. Further, we have shown that acutely increasing adult-born immature neuron (ABIN) activity without an increase in neurogenesis is sufficient to rapidly induce antidepressant effects. The behavioral consequences of increasing ABIN activity occur within hours, whereas the effects of increasing the number of ABINs and their integration into the hippocampal dentate gyrus (DG) take weeks. Most antidepressants have a therapeutic lag of weeks, but earlier onset of antidepressant effects correlates with decreased suicidal behavior and increased likelihood of remission, making rapid-acting antidepressants desirable. At subanesthetic doses, the NMDA receptor antagonist ketamine exerts antidepressant effects within hours and has sustained therapeutic effects lasting weeks. Understanding its mechanisms of action may inform new antidepressants with minimal therapeutic lag and fewer significant adverse effects. Here, I found that ketamine increases both neurogenesis in the DG and the activity of DG neurons, and that ketamine's effects on ABIN activity mediate ketamine's rapid behavioral effects, whereas effects on neurogenesis underlie its longer-term behavioral effects. In Aim 1, I determined the contribution of ABIN activity to ketamine's acute behavioral effects. I defined how silencing ABINs alters ketamine's acute effects in naive mice and mice exposed to unpredictable chronic mild stress (UCMS). To inducibly and specifically silence ABINs, I used Cre-inducible expression of an inhibitory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) in neuronal precursor cells and their progeny. I administered ketamine and determined that neuronal silencing blocks ketamine's rapid effects on mouse anxiety/depression-like behavior. I also determined that AMPA receptor blockade with the drug NBQX inhibits both ketamine's behavioral effects and immature neuron activity, indicating that the effect of ketamine on behavior likely relies on ketamine effects that occur upstream of the neurogenic niche. Finally, I demonstrated that chemogenetically activating ABINs mimics ketamine's effects on mouse affective behavior, suggesting that ABIN activity is both necessary and sufficient for rapid antidepressant effects. In Aim 2, I examined mechanisms of ketamine's sustained effects on neurogenesis and behavior and determined that they depend on a reduction in bone morphogenetic protein (BMP) signaling. Neurogenesis in the DG is inhibited by BMP signaling, and inhibition of BMP signaling increases neurogenesis and exerts an antidepressant effect. The behavioral effects of the Selective Serotonin Receptor Inhibitor (SSRI) fluoxetine are mediated by decreased BMP signaling, and I found that ketamine treatment similarly reduces BMP signaling. By maintaining high BMP signaling in mice exposed to UCMS, administering multiple doses of ketamine, and measuring behavioral effects, I determined that a reduction in BMP signaling is necessary for the longer-term effects that last after treatment cessation. While ketamine use poses its own risks, understanding the mechanisms of its antidepressant effects may inform a new generation of antidepressant medications that induce rapid effects with sustained efficacy, at a minimum until conventional antidepressants with better safety profiles can take effect.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798379588588Subjects--Topical Terms:

593561
Neurosciences.
Subjects--Index Terms:

Dentate gyrusIndex Terms--Genre/Form:

554714
Electronic books.

Mechanisms Mediating the Rapid and Sustained Antidepressant Effects of Ketamine.
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