Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery

Major depressive disorder remains a leading cause of disability, and decades of monoam-ine-centered pharmacology have yielded delayed and often incomplete relief. Rapid-acting antidepressants reshaped the field by linking swift symptom improvement to glu-tamatergic 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 consoli-dation, 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 consoli-dation mediated by tropomyosin receptor kinase B (TrkB) signaling, translational disinhi-bition via eukaryotic elongation factor 2 kinase (eEF2K), and presynaptic stabilization in-dexed by synaptic vesicle glycoprotein 2A (SV2A); together, these processes transform transient potentiation into persistent network change. It then highlights intrinsic excitabil-ity, emphasizing voltage-gated potassium channel subfamily Q (Kv7), hyperpolarization-activated cyclic nucleotide-gated (HCN), and G protein-gated inwardly rectifying potassi-um (GIRK) channels as circuit-level governors that normalize firing and limit relapse-prone hyperexcitability. Finally, it presents a phase-aware Induction–Consolidation–Maintenance (ICM) roadmap, supported by SV2A positron emission tomography (PET) and electroencephalography (EEG)/functional magnetic resonance imaging (fMRI) bi-omarkers, to personalize treatment timing and combinations. This dual-target strategy re-frames antidepressants as network reprogrammers and suggests broader relevance for circuit repair across neurology and psychiatry.