Translational Regulation in Excitatory Neurons Controls Stress Reactivity and the Antidepressant Response to Ketamine

Chronic stress is a major risk factor for major depressive disorder (MDD), while acute stress is adaptive and mediated by hypothalamic-pituitary-adrenal axis activation. Ketamine produces rapid antidepressant effects partly through 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 neurons in behavioural and endocrine responses to acute and chronic stress, and in ketamine's antidepressant effect. Acute stress increased grooming and corticosterone in both sexes, with attenuated grooming in male DKO mice only. Under chronic stress, DKO mice showed resilience to stress-induced behavioural deficits, while ketamine reversed these deficits in control mice. This work deepens understanding of cellular factors controlling stress response and how ketamine produces therapeutic effects.

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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.