Translational Regulation in Excitatory Neurons Controls Stress Reactivity and the Antidepressant Response to Ketamine
Sebastian Baranyi Nicholls
Study at a glance
AI-extracted from the abstract| Characteristics | Thesis |
|---|---|
| Population | Mice |
| Intervention | Ketamine |
| Topics | Ketamine Esketamine |
| Keywords | Excitatory postsynaptic potential Antidepressant Fight-or-flight response Inhibitory postsynaptic potential Reactivity psychology Glutamate receptor Pharmacology Neurotransmitter Nmda receptor Stress linguistics |
| Key points | 4E-BP signalling in excitatory forebrain neurons modulates stress responses and ketamine's antidepressant effects |
Abstract
Major depressive disorder (MDD) is a leading cause of disability worldwide, with nearly one-third remaining treatment-resistant. Chronic stress is a major risk factor for MDD, whereas acute stress is adaptive and mediated by hypothalamic-pituitary-adrenal axis activation. Ketamine produces rapid antidepressant effects, partly through mammalian target of rapamycin complex 1 (mTORC1) signalling, which phosphorylates 4E-Binding Protein 1 and 2 (4E-BPs) to promote synaptic plasticity. This thesis examines the role of 4E-BP signalling in excitatory forebrain (Camk2a-positive) neurons in behavioural and endocrine responses to acute (ARS) and chronic (CVS) stress, and in ketamine's antidepressant effect. We found that ARS increased grooming and corticosterone in both sexes, with attenuated grooming in male DKO mice only. In CVS, DKO mice showed resilience to stress-induced behavioural deficits, while ketamine reversed these deficits in control mice. This work deepens our understanding of cellular factors controlling stress response and how ketamine produces therapeutic effects.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |