860. Glutamatergic Signaling and Neuroplasticity in Mood Disorders: A Historical Perspective from Preclinical Discoveries to Clinical Translation

Abstract Background While the monoaminergic hypothesis has long dominated the treatment of mood disorders, its limitations have prompted the exploration of alternative mechanisms. Early work by Skolnick et al. (1996) demonstrated that chronic antidepressant treatment induces adaptive changes in N-methyl-D-aspartate (NMDA) receptors, suggesting glutamatergic signaling as a convergent pathway in antidepressant action. This framework set the stage for a paradigm shift toward synaptic plasticity as a central mechanism in mood disorders in the last decades. Aims & Objectives The AIM is to present a narrative review integrating preclinical and clinical studies investigating glutamatergic mechanisms in mood disorders, focusing on NMDA and AMPA receptor dynamics, intracellular signaling pathways (including mTORC1 and eIF4E-dependent translation), and circuit-level adaptations. Key translational studies form literature and Gobbi’s lab involving ketamine and serotonergic hallucinogens are included.

Method: Literature review was conducted using Medline, Embase, CINAHL, and PsycInfo from database inception to May 2026. Searches were performed using Covance software, focusing on studies investigating glutamatergic signaling, NMDA and AMPA receptor function, neuroplasticity, and rapid-acting antidepressants. Both preclinical and clinical studies were included.

Results: Preclinical and clinical studies show that stress and depressive-like states are associated with impaired glutamatergic transmission, synaptic atrophy, and reduced dendritic spine density in cortico-limbic regions. Building on the NMDA receptor antagonism hypothesis (Trullas and Skolnik, 1990; Moghaddam, 1993; Skolnick et al., 1996), ketamine was shown to produce rapid antidepressant effects in treatment-resistant depression (Zarate et al., 2006). Mechanistically, ketamine induces NMDA receptor blockade, leading to glutamate surge and enhanced AMPA receptor throughput, a process required for its antidepressant effects (Krystal et al., 2013). At the molecular level, ketamine activates mTORC1 signaling and cell-specific protein synthesis via eIF4E-dependent mechanisms, promoting synaptogenesis (Aguilar-Valles et al., 2021). These effects unfold in a temporally organized manner, linking early synaptic potentiation to sustained structural plasticity. Recent converging evidence indicates that serotonergic psychedelics engage similar glutamatergic plasticity pathways. LSD promotes social behavior and synaptic plasticity via facilitation of the AMPA receptors and mTORC1 in excitatory neurons (De Gregorio et al., 2021, PNAS), and broader work highlights shared mechanisms across LSD, psilocybin, MDMA, and ketamine (De Gregorio et al., 2021, J Neurosci). Recent integrative models further emphasize circuit-level disinhibition and synaptic remodeling as core mechanisms underlying rapid-acting antidepressants (Krystal et al., 2023). Discussion & Conclusions Glutamatergic signaling has emerged as a central framework linking synaptic plasticity to the pathophysiology and treatment of mood disorders. From NMDA receptor adaptations to rapid-acting antidepressants such as ketamine and psychedelics, this paradigm shift redefines mood disorders as disorders of neuroplasticity. Future work should focus on developing safer glutamatergic modulators and biomarker-driven approaches to optimize clinical translation.