A Multiscale View of the Mechanisms Underlying Ketamine's Antidepressant Effects: An Update on Neuronal Calcium Signaling

Abstract

Major depressive disorder (MDD) is a debilitating disease characterized by depressed mood, loss of interest or pleasure, suicidal ideation, and reduced motivation or hopelessness. Despite considerable research, mechanisms underlying MDD remain poorly understood, and current advances in treatment are far from satisfactory. The antidepressant effect of ketamine is among the most important discoveries in psychiatric research over the last half-century. Neurobiological insights into the ketamine's effects have shed light on the mechanisms underlying antidepressant efficacy. However, mechanisms underlying the rapid and sustained antidepressant effects of ketamine remain controversial. Elucidating such mechanisms is key to identifying new therapeutic targets and developing therapeutic strategies. Accumulating evidence demonstrates the contribution of the glutamatergic pathway, the major excitatory neurotransmitter system in the central nervous system, in MDD pathophysiology and antidepressant effects. The hypothesis of a connection among the calcium signaling cascade stimulated by the glutamatergic system, neural plasticity, and epigenetic regulation of gene transcription is further supported by its associations with ketamine's antidepressant effects. This review briefly summarizes the potential mechanisms of ketamine's effects with a specific focus on glutamatergic signaling from a multiscale perspective, including behavioral, cellular, molecular, and epigenetic aspects, to provide a valuable overview of ketamine's antidepressant effects.

Keywords: antidepressant action; calcium signaling; epigenetics; gene expression; glutamate receptor; ketamine; neuroplasticity; stress.

FIGURE 1

Proposed mechanisms of ketamine’s antidepressant action. The binding of ketamine to N-methyl-D-aspartate receptors (NMDARs) on GABAergic interneurons disinhibits glutamatergic neurons, which results in increased synaptic glutamate release. AMPAR activation by glutamate increases brain-derived neurotrophic factor (BDNF) levels. Although the exact source of BDNF is yet to be determined, local release of BDNF is thought to stimulate TrkB receptors. This activation activates intracellular signaling, such as the Ca²⁺ pathway. Another mechanism is the direct inhibition of NMDAR by ketamine. Inhibiting postsynaptic NMDARs reduces eEF2 via the inactivation of CaMK (eEF2 kinase), which leads to enhanced local protein synthesis of BDNF. Increased intracellular Ca²⁺ stimulates CaMKs and their downstream targets, including MeCP2, MEF2, and HDAC5. MeCP2, a transcriptional regulator, binds to methylated CpG sites on the genomic region and interacts with other transcription repressors, including HDACs. CaMKII phosphorylates MeCP2, promotes its nuclear export, and increases activity-dependent transcription. MEF2 recruits HDAC5 and removes activating acetyl groups from histones, which results in a silenced or repressed state of transcription. CaMKII phosphorylates HDAC5, which promotes nuclear export and increases activity-dependent transcription. Ketamine is known to increase the phosphorylation of CaMKII, MeCP2, and HDAC5 (see detail in the main text). Thus, ketamine-mediated enhancement of intracellular Ca²⁺ signaling is linked to epigenetic regulation of transcription, which leads to long-term synaptic plasticity and, consequently, prolonged antidepressant-like effects.