Synaptic Plasticity-Intrinsic Excitability and Antidepressant Discovery

Major depressive disorder remains a leading cause of disability, and decades of monoamine-centered pharmacology have yielded delayed and often incomplete relief. Rapid-acting antidepressants reshaped the field by linking swift symptom improvement to glutamatergic plasticity, yet durable benefit depends on how newly reconfigured circuits are stabilized and tuned. This review synthesizes evidence that antidepressant efficacy arises from the coordinated engagement of synaptic plasticity, spanning induction and consolidation, and intrinsic excitability, which provides gain control, and proposes an integrated framework to guide future discovery. It first outlines induction through N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), exemplified by ketamine and esketamine, followed by consolidation mediated by tropomyosin receptor kinase B (TrkB) signaling, translational disinhibition via eukaryotic elongation factor 2 kinase (eEF2K), and presynaptic stabilization indexed by synaptic vesicle glycoprotein 2A (SV2A); together, these processes transform transient potentiation into persistent network change. It then highlights intrinsic excitability, emphasizing voltage-gated potassium channel subfamily Q (Kv7), hyperpolarization-activated cyclic nucleotide-gated (HCN), and G protein-gated inwardly rectifying potassium (GIRK) channels as circuit-level governors that normalize firing and limit relapse-prone hyperexcitability. Finally, it presents the Induction-Consolidation-Maintenance (ICM) framework as a hypothesis-generating roadmap for future studies, with SV2A positron emission tomography (PET), electroencephalography (EEG), and functional magnetic resonance imaging (fMRI) biomarkers discussed as candidate tools rather than validated guides for treatment timing or patient selection. The proposed contribution is not another list of plasticity pathways, but a phase-specific model that links synaptic induction, consolidation, and excitability-based maintenance to distinct therapeutic windows, biomarkers, and relapse-prevention strategies.