Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery

Major depressive disorder remains a leading cause of disability, and decades of mono-amine-centered pharmacology have yielded delayed and often incomplete relief. Rap-id-acting antidepressants reshaped the field by linking swift symptom improvement to glutamatergic plasticity, yet durable benefit depends on how newly reconfigured cir-cuits are stabilized and tuned. This review synthesizes evidence that antidepressant ef-ficacy arises from the coordinated engagement of synaptic plasticity, spanning induc-tion and consolidation, and intrinsic excitability, which provides gain control, and pro-poses 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 esketa-mine, 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); to-gether, 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), electroen-cephalography (EEG), and functional magnetic resonance imaging (fMRI) biomarkers discussed as candidate tools rather than validated guides for treatment timing or pa-tient 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.